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
Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN8A-specific information. Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1582. In-frame exons: 1, 7, 8, 12, 17, 19, 25 Out-of-frame exons: 2-6, 9-11, 13-16, 18, 20-24, 26 Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”. For splice region variants, this criterion should not be applied with PP3.
Modification Type:
General recommendation
Strong
Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN8A-specific information. Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1582. In-frame exons: 1, 7, 8, 12, 17, 19, 25 Out-of-frame exons: 2-6, 9-11, 13-16, 18, 20-24, 26 Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”. For splice region variants, this criterion should not be applied with PP3.
Modification Type:
General recommendation
Moderate
Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN8A-specific information. Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1582. In-frame exons: 1, 7, 8, 12, 17, 19, 25 Out-of-frame exons: 2-6, 9-11, 13-16, 18, 20-24, 26 Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”. For splice region variants, this criterion should not be applied with PP3.
Modification Type:
General recommendation
Supporting
Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN8A-specific information. Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1582. In-frame exons: 1, 7, 8, 12, 17, 19, 25 Out-of-frame exons: 2-6, 9-11, 13-16, 18, 20-24, 26 Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”. For splice region variants, this criterion should not be applied with PP3.
Modification Type:
General recommendation
Instructions:
Most terminal codon expected to undergo nonsense-mediated decay: p.Thr1582 For splice sites, this criterion should not be applied with PP3. For a full gene deletion, a pathogenic classification is warranted. Not Applicable
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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/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).
Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
Modification Type:
Gene-specific
Moderate
Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).
Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
Modification Type:
Gene-specific,Strength
Supporting
Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).
Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
Modification Type:
Gene-specific
Instructions:
The paralogous sodium channel genes associated with neurodevelomental disorders (SCN1A, SCN2A, SCN3A, SCN8A) share >77% sequence identity (PMID:33531663). The four homologous domains with voltage sensor and pore region remain largely preserved across the channels. Differences lie within the terminal regions and cytoplasmic loops. When these regions are excluded from analysis, homology increases to >90% (PMID:33531663; PMID:16382098). As such, Pathogenic and Likely Pathogenic variants in paralogous genes can be considered for PS1. 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
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 4 points will arrive at Very Strong.
Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.
Modification Type:
Disease-specific,Strength
Strong
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 2 points will arrive at Strong.
Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.
Modification Type:
Disease-specific,Strength
Moderate
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 1 point will arrive at Moderate.
Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.
Modification Type:
Disease-specific,Strength
Supporting
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 0.5 points will arrive at Supporting.
Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.
Modification Type:
Disease-specific,Strength
Instructions:
Complex Neurodevelopmental Disorder (MONDO:0100038), as further described in Helbig et al, 2018 (PMID: 30311377), represents the broad and overlapping clinical spectrum that can include epilepsy, developmental delay, intellectual disability and autism spectrum disorder. 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
Modification Type:
Disease-specific,Gene-specific
Moderate
Modification Type:
Gene-specific,Strength
Supporting
Zebrafish knock-in model displays induced seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies
Modification Type:
Gene-specific,Strength
Instructions:
If a variant is found to have differences from wildtype of multiple levels of strength (example: strong level of evidence in peak current and moderate level of evidence in persistent current), use the highest level of evidence (capping at strong). If a variant has been studied in multiple publications, use the strongest level of evidence available. 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
Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of 16+ points will arrive at Very Strong.
Modification Type:
Disease-specific,Gene-specific,Strength
Strong
Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of 4 - 15.5 points will arrive at Strong.
Modification Type:
Disease-specific,Gene-specific,Strength
Moderate
Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of 2 - 3.5 points will arrive at Moderate.
Modification Type:
Disease-specific,Gene-specific,Strength
Supporting
Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of 1 - 1.5 points will arrive at Supporting.
Modification Type:
Disease-specific,Gene-specific,Strength
Instructions:
Complex Neurodevelopmental Disorder (MONDO:0100038), as further described in Helbig et al, 2018 (PMID: 30311377), represents the broad and overlapping clinical spectrum that can include epilepsy, developmental delay, intellectual disability and autism spectrum disorder. 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
Variant is located within a Pathogenic Enriched Region. See specific amino acid residues noted in the attached “PM1 Table".
Modification Type:
Gene-specific
Supporting
Instructions:
Pathogenic Enriched Regions (PERs): Regions that are enriched for Pathogenic variants (ClinVar/HGMD) across gene families, lack population (gnomAD) variants. Pérez-Palma, 2020 PMID: 31871067 & Lal et al, 2020 PMID: 32183904 Not Applicable
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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
One or fewer alleles, if a minimum of 10,000 alleles assessed in population databases, such as the Genome Aggregation Database (gnomAD). Caveat: Population data for indels may be poorly called by next generation sequencing.
Modification Type:
Other
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
Not Applicable
Comments:
SCN8A is associated with autosomal dominant inheritance.
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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
Moderate
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Modification Type:
No change
Supporting
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
Greater than or equal to 2 known pathogenic variants at same site as novel change (within the same gene). Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
Modification Type:
Disease-specific,Gene-specific,Strength
Moderate
Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
Modification Type:
Disease-specific,Gene-specific
Supporting
Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
Modification Type:
Disease-specific,Gene-specific,Strength
Instructions:
The paralogous sodium channel genes associated with neurodevelomental disorders (SCN1A, SCN2A, SCN3A, SCN8A) share >77% sequence identity (PMID:33531663). The four homologous domains with voltage sensor and pore region remains largely preserved across the channels. Differences lie within the terminal regions and cytoplasmic loops. When these regions are excluded from analysis, homology increases to >90% (PMID:33531663; PMID:16382098). As such, Pathogenic and Likely Pathogenic variants in paralogous genes can be considered for PM5. Rule Combining Stipulation: If PM5_Strong is reached, and the variant falls within a PM1 region, then do not add PM1 with PM5_Strong. 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
Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 2 points will arrive at Strong. Total of 4 points will arrive at Very Strong.
Modification Type:
Disease-specific,Gene-specific,Strength
Moderate
Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 1 point will arrive at Moderate.
Modification Type:
Disease-specific,Gene-specific,Strength
Supporting
Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 0.5 points will arrive at Supporting.
Modification Type:
Disease-specific,Gene-specific,Strength
Instructions:
Complex Neurodevelopmental Disorder (MONDO:0100038), as further described in Helbig et al, 2018 (PMID: 30311377), represents the broad and overlapping clinical spectrum that can include epilepsy, developmental delay, intellectual disability and autism spectrum disorder. 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
>=7 independent meioses
Modification Type:
Strength
Moderate
5-6 independent meioses
Modification Type:
Strength
Supporting
3-4 independent meioses
Modification Type:
Strength
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:
Benign missense variants are common.
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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
Follow ClinGen’s recommendations (PMID: 36413997), using REVEL as the computational tool, with the following stipulations:
Modification Type:
General recommendation,Strength
Supporting
Follow ClinGen’s recommendations (PMID: 36413997), using REVEL as the computational tool, with the following stipulations:
Modification Type:
General recommendation,Strength
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
Not Applicable
Comments:
Phenotypic specificity incorporated into PS2, PM6, PS4
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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
Allele frequency is above 0.01% is gnomAD or other large population databases, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.
Modification Type:
Disease-specific
Very Strong
Strong
Moderate
Supporting
Instructions:
Allele frequency is above 0.02% in GnomAD or other large population database. Not Applicable
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BS1 | ||||
Original ACMG Summary
Allele frequency is greater than expected for disorder.
Stand Alone
Very Strong
Strong
Allele frequency is above 0.0002% in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.
Modification Type:
Disease-specific,Gene-specific
Moderate
Supporting
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 with full penetrance expected at an early age.
Modification Type:
No change
Moderate
Supporting
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:
Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies.
This can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.
Animal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic intellectual disability and/or autism spectrum disorder, are still being established and could support pathogenicity.
This can be re-assessed by the EP over time.
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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
Moderate
Supporting
Not Applicable
Comments:
Reduced penetrance and phenocopies
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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:
Missense variants are common cause of disease.
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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
Moderate
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
In frame-deletions/insertions in a repetitive region without a known function.
Modification Type:
No change
Not Applicable
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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
Follow ClinGen’s recommendations (PMID: 36413997), using REVEL as the computational tool.
Modification Type:
General recommendation
Supporting
Follow ClinGen’s recommendations (PMID: 36413997), using REVEL as the computational tool.
Modification Type:
General recommendation
Not Applicable
Comments:
Replicating methodologies by Pejaver et al, 2022 and Johnston et al, 2021 (PMID: 33767344), REVEL scores could not be obtained for Benign calculations.
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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
Moderate
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 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.
Modification Type:
No change
Not Applicable
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