Criteria Specification (CSpec) Registry is intended to provide access to the Criteria Specifications used and applied by ClinGen Variant Curation Expert Panels and biocurators in the classification of variants.
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Criteria & Strength Specifications
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PVS1 | ||||
Original ACMG Summary
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. Stand Alone
Very Strong
Strong
Moderate
Supporting
Instructions:
RYR1 is associated with both dominant and recessive myopathy. Loss of function is only a mechanism for autosomal recessive (AR) disease and PVS1 should only be applied for AR variants. Not Applicable
Comments:
Loss of function is not a mechanism of disease for autosomal dominant RYR1-related myopathy.
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PS1 | ||||
Original ACMG Summary
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. Stand Alone
Very Strong
Strong
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.
Modification Type:
No change
Moderate
No change - use as originally described
Modification Type:
No change
Supporting
No change - use as originally described
Modification Type:
No change
Not Applicable
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PS2 | ||||
Original ACMG Summary
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. Stand Alone
Very Strong
No change - use as originally described
Modification Type:
No change
Strong
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.
Modification Type:
No change
Moderate
No change - use as originally described
Modification Type:
No change
Supporting
No change - use as originally described
Modification Type:
No change
Not Applicable
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PS3 | ||||
Original ACMG Summary
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. Stand Alone
Very Strong
Strong
Strong may only be considered for variant-specific mouse models. Currently, no other assays are applicable at this strength.
Modification Type:
Disease-specific
Moderate
Some of the assays from PS3_Supporting may be stacked to reach a Moderate Strength. One specific assay is currently suggested to be applied at Moderate: Calcium Release**: An abnormal readout consists of increased calcium release compared to controls or WT RYR1. **Calcium Release assays and Single Channel Activity assays should not be stacked because they may not be assessing independent biological function.
Modification Type:
Gene-specific
Supporting
Two specific assays are currently suggested to be applied at Supporting:
If not listed above, it is acceptable to use PS3_Supporting for other functional analyses if
**Calcium Release assays and Single Channel Activity assays should not be stacked because they may not be assessing independent biological function.
Modification Type:
Gene-specific
Instructions:
**Calcium Release assays and Single Channel Activity assays should not be stacked because they may not be assessing independent biological function. Not Applicable
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PS4 | ||||
Original ACMG Summary
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. Stand Alone
Very Strong
Strong
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. RYR1 is associated with both autosomal recessive and autosomal dominant disease. If you are curating biallelic observations, please use the AR specifications. For case counting for AD disease, please see the PS4 chart. at least 1 point, please see PS4 chart
Modification Type:
Disease-specific,Gene-specific
Moderate
0.5 points, please see PS4 chart
Modification Type:
Disease-specific,Gene-specific
Supporting
0.25 points, please see PS4 chart
Modification Type:
Disease-specific,Gene-specific
Instructions:
RYR1 is associated with both autosomal recessive and autosomal dominant disease. If you are curating biallelic observations, please use the AR specifications. For case counting for AD disease, please see the PS4 chart. Not Applicable
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PM1 | ||||
Original ACMG Summary
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
Stand Alone
Very Strong
Strong
Moderate
The pore/transmembrane region of RYR1 is critical for protein function and missense variants that fall within this region (amino acids 4800-4950)
Modification Type:
Disease-specific,Gene-specific
Supporting
Not Applicable
Comments:
There are no defined hotspots or critical functional domains in ACTA1 at this time.
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PM2 | ||||
Original ACMG Summary
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. Stand Alone
Very Strong
Strong
Moderate
Supporting
PM2_Supporting may be applied if the minor allele frequency in population databases of at least 2000 alleles is absent (1 allele allowed) for autosomal dominant
Modification Type:
Disease-specific,Gene-specific
Instructions:
If the mode of inheritance for the variant is unclear (largely with missense variants as loss of function variants are predicted to cause AR disease), use the more conservative AD specifications and cutoff for PM2_Supporting Not Applicable
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PM3 | ||||
Original ACMG Summary
For recessive disorders, detected in trans with a pathogenic variant
Note: This requires testing of parents (or offspring) to determine phase. Stand Alone
Very Strong
Strong
Moderate
Supporting
Instructions:
Please use this SVI-recommended PM3 chart to count observations. Points for each proband should be summed to get to a final PM3 strength. In order to count to count case counts for your variant of interest, it should be rare enough to not meet BS1. For variants that follow an autosomal dominant mode of inheritance, please use PS4 for case counting. Not Applicable
Comments:
Biallelic cases should not be counted using the RYR1 autosomal dominant specifications. Please see the autosomal recessive specifications for use of PM3.
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PM4 | ||||
Original ACMG Summary
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Stand Alone
Very Strong
Strong
No change - use as originally described
Modification Type:
No change
Moderate
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Modification Type:
No change
Supporting
No change - use as originally described
Modification Type:
No change
Instructions:
If a variant is shown to be a loss of function variant, AR specifications should be used. Not Applicable
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PM5 | ||||
Original ACMG Summary
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. Stand Alone
Very Strong
Strong
No change - use as originally described
Modification Type:
No change
Moderate
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.
Modification Type:
No change
Supporting
No change - use as originally described
Modification Type:
No change
Not Applicable
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PM6 | ||||
Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Stand Alone
Very Strong
Strong
No change - use as originally described
Modification Type:
No change
Moderate
Assumed de novo, but without confirmation of paternity and maternity.
Modification Type:
No change
Supporting
No change - use as originally described
Modification Type:
No change
Not Applicable
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PP1 | ||||
Original ACMG Summary
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. Stand Alone
Very Strong
Strong
See segregation chart
Modification Type:
General recommendation
Moderate
See segregation chart
Modification Type:
General recommendation
Supporting
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. See segregation chart
Modification Type:
General recommendation
Instructions:
The segregation chart (adopted from Oza et al 2018 PMID:30311386) should be used to determine the strength level of the total number of affected and unaffected segregations. In order to count unaffected segregations, the unaffected individuals can be heterozygous carriers or WT, but should have the same risk of inheriting the variant as the affected individuals (e.g. siblings in the same generation). Not Applicable
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PP2 | ||||
Original ACMG Summary
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
Stand Alone
Very Strong
Strong
Moderate
Supporting
Not Applicable
Comments:
RYR1 is not a gene that is constrained for missense variation. Hence PP2 is not applicable.
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PP3 | ||||
Original ACMG Summary
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. Stand Alone
Very Strong
Strong
Moderate
Supporting
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. PP3 is met if the REVEL score ≥ 0.7 or if the variant is predicted to impact splicing using SpliceAI score ≥0.5
Modification Type:
General recommendation
Not Applicable
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PP4 | ||||
Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Stand Alone
Very Strong
Strong
Moderate
Supporting
Instructions:
PP4 cannot be used in combination with PS4 for AD variants. This can only be used in combination with PM3 for AR variants Not Applicable
Comments:
PP4 is factored into the weight of PS4 case counting and should not be applied separately.
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PP5 | ||||
Original ACMG Summary
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 | ||||
Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Stand Alone
The minor allele frequency using the filtering allele frequency of either exomes or genomes of continental populations in gnomAD is ≥0.0000486 for AD variants. All populations used should have at least 2000 alleles and >1 observation. BA1 exclusion variants (well-known pathogenic variants that are above the specified BA1 or BS1 threshold) are as follows: NM_000540.3:c.14524G>A (p.Val4842Met) NM_000540.3:c.325C>T (p.Arg109Trp)
Modification Type:
Disease-specific,Gene-specific
Very Strong
Strong
Moderate
Supporting
Instructions:
If the mode of inheritance for the variant is unclear (this largely applies to missense variants as loss of function variants are suspected to cause AR disease), use the more conservative AR cutoff for BA1 and the AR specifications. Not Applicable
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BS1 | ||||
Original ACMG Summary
Allele frequency is greater than expected for disorder.
Stand Alone
Very Strong
Strong
The minor allele frequency using the filtering allele frequency of either exomes or genomes of continental populations in gnomAD is ≥0.00000486 for AD variants. All populations used should have at least 2000 alleles and >1 observation. BA1/BS1 exclusion variants (well-known pathogenic variants that are above the specified BA1 or BS1 threshold) are as follows: NM_000540.3:c.14524G>A (p.Val4842Met) NM_000540.3:c.325C>T (p.Arg109Trp)
Modification Type:
Disease-specific,Gene-specific
Moderate
Supporting
Instructions:
If the mode of inheritance for the variant is unclear (this largely applies to missense variants as loss of function variants are suspected to cause AR disease), use the more conservative AR cutoff for BS1 and the AR specifcations. Not Applicable
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BS2 | ||||
Original ACMG Summary
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.
Stand Alone
Very Strong
Strong
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.
Modification Type:
No change
Moderate
No change - use as originally described
Modification Type:
No change
Supporting
No change - use as originally described
Modification Type:
No change
Not Applicable
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BS3 | ||||
Original ACMG Summary
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
Stand Alone
Very Strong
Strong
Moderate
Supporting
Not Applicable
Comments:
The VCEP has decided that lack of demonstrated effect in a functional assay should not count against the pathogenicity of an RYR1 variant because of the numerous possible functions of the ryanodine receptor; therefore all specified functional assays will only be used as evidence for pathogenicity.
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BS4 | ||||
Original ACMG Summary
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. Stand Alone
Very Strong
Strong
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.
Modification Type:
No change
Moderate
No change - use as originally described
Modification Type:
No change
Supporting
No change - use as originally described
Modification Type:
No change
Not Applicable
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BP1 | ||||
Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Stand Alone
Very Strong
Strong
Moderate
Supporting
Not Applicable
Comments:
Both missense and truncating variants in RYR1 are disease-causing.
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BP2 | ||||
Original ACMG Summary
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.
Stand Alone
Very Strong
Strong
No change - use as originally described
Modification Type:
No change
Moderate
No change - use as originally described
Modification Type:
No change
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.
Modification Type:
No change
Not Applicable
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BP3 | ||||
Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Stand Alone
Very Strong
Strong
Moderate
Supporting
Not Applicable
Comments:
There are no regions in RYR1 where BP3 would apply.
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BP4 | ||||
Original ACMG Summary
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. Stand Alone
Very Strong
Strong
Moderate
Supporting
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. BP4 is met if the REVEL score ≤ 0.15 or if the variant is not predicted to impact splicing using SpliceAI.
Modification Type:
General recommendation
Not Applicable
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BP5 | ||||
Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Stand Alone
Very Strong
Strong
No change - use as originally described
Modification Type:
No change
Moderate
No change - use as originally described
Modification Type:
No change
Supporting
Variant found in a case with an alternate molecular basis for disease.
Modification Type:
No change
Not Applicable
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BP6 | ||||
Original ACMG Summary
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 | ||||
Original ACMG Summary
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.
Stand Alone
Very Strong
Strong
Moderate
Supporting
A synonymous variant for which SpliceAI predicts no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
Modification Type:
General recommendation
Not Applicable
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