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ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_ntDNA
Criteria | Original ACMG Summary | Strength Specifications | |||||
---|---|---|---|---|---|---|---|
  PVS1 | Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Caveats: • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7). • Use caution interpreting LOF variants at the extreme 3’ end of a gene. • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact. • Use caution in the presence of multiple transcripts. |
Very Strong
Applied per PVS1 flowsheet of Abou Toyoun et al.
|
|||||
  PS1 | Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. |
Strong
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change
|
|||||
  PS2 | De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. |
Strong
De novo in a patient with the disease and no family history
|
|||||
  PS3 | Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established. |
Supporting
Transporter assay showing loss of function
|
|||||
  PS4 | The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence. |
Not Applicable
|
|||||
  PM1 | Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. |
Not Applicable
|
|||||
  PM2 | Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Caveat: Population data for indels may be poorly called by next generation sequencing. |
Moderate
<0.00005 (<0.0050%)
|
|||||
  PM3 | For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase. |
Moderate
Use per SVI guidance
|
|||||
  PM4 | Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. |
Moderate
Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants
|
|||||
  PM5 | Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. |
Moderate
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
|
|||||
  PM6 | Assumed de novo, but without confirmation of paternity and maternity. |
Strong
De novo in a patient with the disease and no family history
Moderate
Assumed de novo, but without confirmation of paternity and maternity
|
|||||
  PP1 | Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. Note: May be used as stronger evidence with increasing segregation data. |
Supporting
For segregation, an affected is defined as an individual who
1) has brainstem or basal ganglia lesions compatible with SLC19A3-related Biotin-responsive basal ganglia disease OR 2) a person with neurodevelopmental regression or MRI lesions compatible with SLC19A3-related Biotin-responsive basal ganglia disease who had significant clinical improvement in either symptoms or MRI lesions from treatment with biotin and thiamine. |
|||||
  PP2 | Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. |
Not Applicable
|
|||||
  PP3 | Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant. |
Supporting
No gene-specific predictors; agree to utilize REVEL, with thresholds of >0.75 and <0.15 for PP3 and BP4, respectively
|
|||||
  PP4 | Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology. |
Supporting
Patient has/had MRI features of Leigh syndrome with clinical response to biotin/thiamine
|
|||||
  PP5 | Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation. |
Not Applicable
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
PubMed : 29543229
|
|||||
  BA1 | Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. |
Stand Alone
>0.001 (>0.1%)
|
|||||
  BS1 | Allele frequency is greater than expected for disorder. |
Strong
>0.0005 (>0.050%)
|
|||||
  BS2 | Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. |
Strong
Observed in a healthy, untreated, adult individual in the homozygous state
|
|||||
  BS3 | Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing. |
Supporting
Transporter assay showing no effect on the gene or gene product
|
|||||
  BS4 | Lack of segregation in affected members of a family. Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation. |
Strong
Lack of segregation in affected and/or treated members of a family.
|
|||||
  BP1 | Missense variant in a gene for which primarily truncating variants are known to cause disease. |
Not Applicable
|
|||||
  BP2 | Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern. |
Supporting
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern
|
|||||
  BP3 | In frame-deletions/insertions in a repetitive region without a known function. |
Supporting
In-frame deletions/insertions in a repetitive region without a known function
|
|||||
  BP4 | Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant. |
Supporting
No gene-specific predictors; agree to utilize REVEL, with thresholds of >0.75 and <0.15 for PP3 and BP4, respectively
|
|||||
  BP5 | Variant found in a case with an alternate molecular basis for disease. |
Supporting
Variant found in a case with an alternate molecular basis for disease
|
|||||
  BP6 | Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. |
Not Applicable
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
PubMed : 29543229
|
|||||
  BP7 | A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. |
Supporting
A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
|
Criteria | Original ACMG Summary | Strength Specifications | |||||
---|---|---|---|---|---|---|---|
  PVS1 | Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Caveats: • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7). • Use caution interpreting LOF variants at the extreme 3’ end of a gene. • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact. • Use caution in the presence of multiple transcripts. |
Very Strong
Applied per PVS1 flowsheet of Abou Toyoun et al.
|
|||||
  PS1 | Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. |
Strong
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change
|
|||||
  PS2 | De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. |
Strong
De novo in a patient with the disease and no family history
|
|||||
  PS3 | Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established. |
Not Applicable
|
|||||
  PS4 | The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence. |
Not Applicable
|
|||||
  PM1 | Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. |
Moderate
Located in one of the following functional domains:
• thiamine pyrophosphate (TPP) binding site (aa positions 118Y, 119R, 165G, 167V, 195G, 196D, 197G, 198A, 225N, 227Y, 292H). • α β heterodimer interface (aa positions 160F, 162G, 164N, 169A, 172P, 173L, 176G, 177I, 179L, 180A,183Y, 202G,203Q, 209N, 210M, 213L). • α2 β2 heterotetramer interface (aa positions 88R, 140G, 165G, 166I, 197G, 199A, 200N, 201Q, 202G, 205F, 209N, 213L, 228G, 229M, 230G, 231T, 245R, 296D, 300S). • Phosphorylation loop region (aa positions 287Y, 288R, 289Y, 290H, 291G, 292H, 293S, 295S, 296D, 297P, 298G, 299V, 300S, 301Y, 302R, 303T, 304R, 305E, 314S, 315D, 316P). |
|||||
  PM2 | Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Caveat: Population data for indels may be poorly called by next generation sequencing. |
Moderate
0.0000092 (<0.00092%)
|
|||||
  PM3 | For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase. |
Not Applicable
|
|||||
  PM4 | Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. |
Moderate
Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants
|
|||||
  PM5 | Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. |
Moderate
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
|
|||||
  PM6 | Assumed de novo, but without confirmation of paternity and maternity. |
Strong
De novo in a patient with the disease and no family history
Moderate
Assumed de novo, but without confirmation of paternity and maternity
|
|||||
  PP1 | Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. Note: May be used as stronger evidence with increasing segregation data. |
Supporting
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease
|
|||||
  PP2 | Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. |
Not Applicable
|
|||||
  PP3 | Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant. |
Supporting
No gene-specific predictors; agree to utilize REVEL, with thresholds of >0.75 and <0.15 for PP3 and BP4, respectively
|
|||||
  PP4 | Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology. |
Supporting
One of the following criteria are met:
(1) Pyruvate radioactive enzyme assay showing decreased (as defined as <3rd percentile of controls) for PDC, activated and decreased ratios (PDC/E3 and/or PDC/CS) in fibroblasts, muscle, and/or lymphocytes; (2) other assays showing decrease in PDC activity (ie: western blot, immunocapture, and activity; commercial kits for research); (3) abnormally high pyruvate and/or pyruvate/lactate ratio |
|||||
  PP5 | Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation. |
Not Applicable
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
PubMed : 29543229
|
|||||
  BA1 | Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. |
Stand Alone
>0.00092 (>0.092%)
|
|||||
  BS1 | Allele frequency is greater than expected for disorder. |
Strong
>0.000092 (>0.0092%)
|
|||||
  BS2 | Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. |
Strong
Observed in at least two healthy male adults. Note: Individual’s phenotype is well-characterized (not just seen in database of presumed healthy individuals) AND/OR ≥16 hemizygotes in gnomAD
Supporting
Observed in 4-15 hemizygotes in gnomAD AND/OR Pyruvate radioactive enzyme assay showing normal (defined as >3rd percentile of controls) for PDC, activated and normal ratios (PDC/E3 and/or PDC/CS) in fibroblasts with no evidence of skewed X-inactivation in fibroblasts.
|
|||||
  BS3 | Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing. |
Not Applicable
|
|||||
  BS4 | Lack of segregation in affected members of a family. Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation. |
Strong
Lack of segregation in affected and/or treated members of a family.
|
|||||
  BP1 | Missense variant in a gene for which primarily truncating variants are known to cause disease. |
Not Applicable
|
|||||
  BP2 | Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern. |
Not Applicable
|
|||||
  BP3 | In frame-deletions/insertions in a repetitive region without a known function. |
Supporting
In-frame deletions/insertions in a repetitive region without a known function
|
|||||
  BP4 | Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant. |
Supporting
No gene-specific predictors; agree to utilize REVEL, with thresholds of >0.75 and <0.15 for PP3 and BP4, respectively
|
|||||
  BP5 | Variant found in a case with an alternate molecular basis for disease. |
Supporting
Variant found in a case with an alternate molecular basis for disease
|
|||||
  BP6 | Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. |
Not Applicable
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
PubMed : 29543229
|
|||||
  BP7 | A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. |
Supporting
A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
|
Criteria | Original ACMG Summary | Strength Specifications | |||||
---|---|---|---|---|---|---|---|
  PVS1 | Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Caveats: • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7). • Use caution interpreting LOF variants at the extreme 3’ end of a gene. • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact. • Use caution in the presence of multiple transcripts. |
Very Strong
Applied per PVS1 flowsheet of Abou Toyoun et al.
|
|||||
  PS1 | Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. |
Strong
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change
|
|||||
  PS2 | De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. |
Strong
De novo in a patient with the disease and no family history
|
|||||
  PS3 | Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established. |
Not Applicable
|
|||||
  PS4 | The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence. |
Strong
Rarely, pathogenic variants cause disease in an AD manner. For these variants only, presence in: 2 unrelated probands will be considered supporting evidence, 4 unrelated probands will be considered moderate evidence, 16 unrelated probands will be strong evidence.
• Note: This will only be utilized when there is segregation evidence supporting autosomal dominant inheritance |
|||||
  PM1 | Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. |
Not Applicable
|
|||||
  PM2 | Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Caveat: Population data for indels may be poorly called by next generation sequencing. |
Moderate
<0.0005 (<0.05% )
|
|||||
  PM3 | For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase. |
Moderate
Use per SVI guidance.
Note: T251I and P587L are almost always in cis |
|||||
  PM4 | Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. |
Moderate
Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants
|
|||||
  PM5 | Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. |
Moderate
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
|
|||||
  PM6 | Assumed de novo, but without confirmation of paternity and maternity. |
Strong
De novo in a patient with the disease and no family history
Moderate
Assumed de novo, but without confirmation of paternity and maternity
|
|||||
  PP1 | Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. Note: May be used as stronger evidence with increasing segregation data. |
Supporting
Further define “affected” as an individual in whom there is objective evidence of manifestations consistent with POLG-related disorders spectrum: Alpers-Huttenlocher syndrome (AHS), childhood myocerebrohepatopathy spectrum (MCHS), myoclonic epilepsy myopathy sensory ataxia (MEMSA), ataxia neuropathy spectrum (ANS), and/or progressive external ophthalmoplegia (PEO)
|
|||||
  PP2 | Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. |
Not Applicable
|
|||||
  PP3 | Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant. |
Supporting
Agree to utilize REVEL, with thresholds of >0.75 and <0.15 for PP3 and BP4, respectively
• Will also utilize POLG pathogenicity prediction server if/when live again (PMID: 28480171); both tools (REVEL and server) will have to be in agreement to score |
|||||
  PP4 | Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology. |
Moderate
1. Mitochondrial DNA depletion showing ≤ 20% of controls, OR
2. Multiple mitochondrial DNA deletions (NOTE:depletion and/or deletion analysis must be performed in muscle and/or liver; other tissues such as blood, fibroblast, and buccal are not acceptable; Must be performed in child, as defined as <18 years old) Note: For both scenarios 1 and 2, will only apply if other mtDNA maintenance disorders have been excluded (exome sequencing or comprehensive panel-based testing) Supporting
1. Mitochondrial DNA depletion showing 20-50% of controls in children (< 18 years of age), AND/OR
2. COX negative fibers in muscle in children and/or adults Note: Will only apply if other mtDNA maintenance disorders have been excluded (exome sequencing or comprehensive panel-based testing) |
|||||
  PP5 | Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation. |
Not Applicable
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
PubMed : 29543229
|
|||||
  BA1 | Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. |
Stand Alone
>0.01 (>1%)
|
|||||
  BS1 | Allele frequency is greater than expected for disorder. |
Strong
>0.005 (>0.5% - AR)
|
|||||
  BS2 | Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. |
Strong
Observed in a healthy adult individual in the homozygous state AND/OR Normal mtDNA content (1. Must be performed in muscle and/or liver; blood, fibroblast, and buccal not acceptable; 2. Must be performed in children only - defined as <18 years old; 3. A normal level is defined as >50%.)
Supporting
Lack of COX negative fibers in muscle (children and adults)
|
|||||
  BS3 | Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing. |
Not Applicable
|
|||||
  BS4 | Lack of segregation in affected members of a family. Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation. |
Strong
Lack of segregation in affected and/or treated members of a family.
|
|||||
  BP1 | Missense variant in a gene for which primarily truncating variants are known to cause disease. |
Not Applicable
|
|||||
  BP2 | Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern. |
Supporting
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern
|
|||||
  BP3 | In frame-deletions/insertions in a repetitive region without a known function. |
Supporting
In-frame deletions/insertions in a repetitive region without a known function
|
|||||
  BP4 | Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant. |
Supporting
Agree to utilize REVEL, with thresholds of >0.75 and <0.15 for PP3 and BP4, respectively. Will also utilize POLG pathogenicity prediction server if/when live again (PMID: 28480171); both tools (REVEL and server) will have to be in agreement to score
|
|||||
  BP5 | Variant found in a case with an alternate molecular basis for disease. |
Supporting
Variant found in a case with an alternate molecular basis for disease
|
|||||
  BP6 | Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. |
Not Applicable
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
PubMed : 29543229
|
|||||
  BP7 | A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. |
Supporting
A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
|
Criteria | Original ACMG Summary | Strength Specifications | |||||
---|---|---|---|---|---|---|---|
  PVS1 | Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Caveats: • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7). • Use caution interpreting LOF variants at the extreme 3’ end of a gene. • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact. • Use caution in the presence of multiple transcripts. |
Very Strong
Applied per PVS1 flowsheet of Abou Toyoun et al.
|
|||||
  PS1 | Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. |
Strong
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change
|
|||||
  PS2 | De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. |
Strong
De novo in a patient with the disease and no family history
|
|||||
  PS3 | Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established. |
Supporting
Reduced ETHE1 persulfide dioxygenase
|
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  PS4 | The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence. |
Not Applicable
|
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  PM1 | Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. |
Not Applicable
|
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  PM2 | Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Caveat: Population data for indels may be poorly called by next generation sequencing. |
Moderate
<0.00002 (<0.0020%)
|
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  PM3 | For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase. |
Moderate
Use per SVI guidance
|
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  PM4 | Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. |
Moderate
Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants
|
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  PM5 | Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. |
Moderate
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
|
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  PM6 | Assumed de novo, but without confirmation of paternity and maternity. |
Strong
De novo in a patient with the disease and no family history
Moderate
Assumed de novo, but without confirmation of paternity and maternity
|
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  PP1 | Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. Note: May be used as stronger evidence with increasing segregation data. |
Supporting
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease
|
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  PP2 | Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. |
Not Applicable
|
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  PP3 | Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant. |
Supporting
No gene-specific predictors; agree to utilize REVEL, with thresholds of >0.75 and <0.15 f or PP3 and BP4, respectively
|
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  PP4 | Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology. |
Moderate
Individual has abnormally high urinary ethylmalonic acid AND one of the following:
(1) All of the following symptoms present: -Acrocyanosis -Petechiae -Chronic diarrhea -Developmental delay (2) ≥3 or more of the following biochemical studies: -Abnormally high blood C4-Acylcarnitine esters -Abnormally high blood C5-acylcarnitine -Abnormally high plasma thiosulphate -Abnormally low cytochrome oxidase activity in skeletal muscle (without evidence of other complexes decreased) Supporting
Individual has abnoramlly high urinary ethylmalonic acid AND one of the following:
(1) 3 of the following features present: -Acrocyanosis -Petechiae -Chronic diarrhea -Developmental delay (2) abnormal laboratory studies in 2 of the following biochemical studies: -Abnormally high blood C4-Acylcarnitine esters -Abnormally high blood C5-acylcarnitine -Abnormally high plasma thiosulphate -Abnormally low cytochrome oxidase activity in skeletal muscle, without evidence of other complexes decreased |
|||||
  PP5 | Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation. |
Not Applicable
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
PubMed : 29543229
|
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  BA1 | Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. |
Stand Alone
>0.001 (>0.1%)
|
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  BS1 | Allele frequency is greater than expected for disorder. |
Strong
>0.0002 (>0.020%)
|
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  BS2 | Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. |
Strong
Observed in a healthy adult individual in the homozygous state
Supporting
Normal laboratory values (specific labs outlined in PP4)
|
|||||
  BS3 | Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing. |
Not Applicable
|
|||||
  BS4 | Lack of segregation in affected members of a family. Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation. |
Strong
Lack of segregation in affected and/or treated members of a family.
|
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  BP1 | Missense variant in a gene for which primarily truncating variants are known to cause disease. |
Not Applicable
|
|||||
  BP2 | Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern. |
Supporting
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern
|
|||||
  BP3 | In frame-deletions/insertions in a repetitive region without a known function. |
Supporting
In-frame deletions/insertions in a repetitive region without a known function
|
|||||
  BP4 | Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant. |
Supporting
No gene-specific predictors; agree to utilize REVEL, with thresholds of >0.75 and <0.15 f or PP3 and BP4, respectively
|
|||||
  BP5 | Variant found in a case with an alternate molecular basis for disease. |
Supporting
Variant found in a case with an alternate molecular basis for disease
|
|||||
  BP6 | Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. |
Not Applicable
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
PubMed : 29543229
|
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  BP7 | A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. |
Supporting
A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
|
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