Criteria Specification Registry

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 Specification

ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN2A Version 1.0.0

Description : SCN2A

Version : 1.0.0

Epilepsy Sodium Channel VCEP

Released

3/19/2024

18:41:33

Rules for SCN2A

Gene: SCN2A (HGNC:10588) HGNC Name: sodium voltage-gated channel alpha subunit 2 Transcripts: NM_021007.2 Disease: complex neurodevelopmental disorder (MONDO:0100038) Mode of Inheritance: Autosomal dominant inheritance

Criteria & Strength Specifications
PVS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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 SCN2A-specific information. Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1591. In-frame exons: 1, 7, 8, 12, 17, 25 Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 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: No change Strong Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN2A-specific information. Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1591. In-frame exons: 1, 7, 8, 12, 17, 25 Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 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: No change Moderate Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN2A-specific information. Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1591. In-frame exons: 1, 7, 8, 12, 17, 25 Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 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: No change Supporting Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN2A-specific information. Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1591. In-frame exons: 1, 7, 8, 12, 17, 25 Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 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: No change Instructions: Most terminal codon expected to undergo nonsense-mediated decay: p.Thr1591 For splice sites, this criterion should not be applied with PP3. For a full gene deletion, a pathogenic classification is warranted. Not Applicable
PS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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 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. >1 Identical amino acid change in paralogous gene previously established as Pathogenic or Likely Pathogenic, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions. Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement ("PS1_Variants impacting splicing"). 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 amino acid change as a previously established Likely Pathogenic variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement ("PS1_Variants impacting splicing"). 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). A single identical amino acid change in a paralogous gene previously established as Pathogenic or Likely Pathogenic, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions. Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement ("PS1_Variants impacting splicing"). Modification Type: Disease-specific,Strength Instructions: The paralogous sodium channel genes associated with neurodevelopmental 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. PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859. Not Applicable
PS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Complex Neurodevelopmental Disorder: 1 points Other phenotypes not consistent w/neurodevelopmental disorder: 0 points 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. Complex Neurodevelopmental Disorder: 1 points Other phenotypes not consistent w/neurodevelopmental disorder: 0 points 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. Complex Neurodevelopmental Disorder: 1 points Other phenotypes not consistent w/neurodevelopmental disorder: 0 points 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. Complex Neurodevelopmental Disorder: 1 points Other phenotypes not consistent w/neurodevelopmental disorder: 0 points 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 by 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
PS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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 In patch clamping experiments: Peak current as defined by FENICS ontology (https://bioportal.bioontology.org/ontologies/FENICS) is less than or equal to 72.7% of wildtype. In patch clamping experiments: Persistent current as defined by FENICS ontology (https://bioportal.bioontology.org/ontologies/FENICS) is greater than or equal to 135% of wildtype. In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology (https://bioportal.bioontology.org/ontologies/FENICS) is shifted by at least 2.2 mV (absolute value). In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology (https://bioportal.bioontology.org/ontologies/FENICS) is shifted by at least 4.1 mV (absolute value). Mouse knock-in model displays spontaneous seizures. Modification Type: Disease-specific,Gene-specific Moderate In patch clamping experiments: Peak current as defined by FENICS ontology (https://bioportal.bioontology.org/ontologies/FENICS) is less than or equal to 80.6% of wildtype. In patch clamping experiments: Persistent current as defined by FENICS ontology (https://bioportal.bioontology.org/ontologies/FENICS) is greater than or equal to 125% of wildtype. In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology (https://bioportal.bioontology.org/ontologies/FENICS) is shifted by at least 2.1 mV (absolute value). In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology (https://bioportal.bioontology.org/ontologies/FENICS) is shifted by at least 3.0 mV (absolute value). Zebrafish knock-in model displays spontaneous seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies 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
PS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Complex Neurodevelopmental Disorder: 1 points Other phenotypes not consistent w/neurodevelopmental disorder: 0 points 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. Complex Neurodevelopmental Disorder: 1 points Other phenotypes not consistent w/neurodevelopmental disorder: 0 points Modification Type: Disease-specific,Gene-specific 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. Complex Neurodevelopmental Disorder: 1 points Other phenotypes not consistent w/neurodevelopmental disorder: 0 points 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. Complex Neurodevelopmental Disorder: 1 points Other phenotypes not consistent w/neurodevelopmental disorder: 0 points Modification Type: Disease-specific,Gene-specific,Strength Instructions: Complex Neurodevelopmental Disorder (MONDO:0100038), as further described by 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
PM1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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
PM2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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
PM3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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: SCN2A is associated with autosomal dominant inheritance.
PM4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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
PM5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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 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: Disease-specific,Gene-specific Supporting Novel missense change at an amino acid residue where a different missense change determined to be Likely Pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. >1 Non-Identical aa change in paralogous gene(s) where a different missense change determined to be Pathogenicor Likely Pathogenic, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A) 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
PM6 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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. Complex Neurodevelopmental Disorder: 0.5 points Other phenotypes not consistent w/neurodevelopmental disorder: 0 points 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. Complex Neurodevelopmental Disorder: 0.5 points Other phenotypes not consistent w/neurodevelopmental disorder: 0 points 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. Complex Neurodevelopmental Disorder: 0.5 points Other phenotypes not consistent w/neurodevelopmental disorder: 0 points Modification Type: Disease-specific,Gene-specific,Strength Instructions: Complex Neurodevelopmental Disorder (MONDO:0100038), as further described by 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
PP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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
PP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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.
PP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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: Strength should be capped at Moderate, and limit the combination of PP3 and PM1 to reach no higher than strong Modification Type: General recommendation,Strength Supporting Follow ClinGen’s recommendations (PMID: 36413997), using REVEL as the computational tool, with the following stipulations: Strength should be capped at Moderate, and limit the combination of PP3 and PM1 to reach no higher than strong Modification Type: General recommendation,Strength Not Applicable
PP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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
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
BA1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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
BS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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
BS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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
BS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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 ID/ASD, are still being established and could support pathogenicity. This can be re-assessed by the EP over time.
BS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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
BP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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.
BP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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
BP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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
BP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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.
BP5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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
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
BP7 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
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

Rules for Combining Criteria

Pathogenic

1 Very Strong (PVS1, PS2_Very Strong, PS4_Very Strong) AND ≥ 1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM5_Strong, PM6_Strong, PP1_Strong, PP3_Strong)

1 Very Strong (PVS1, PS2_Very Strong, PS4_Very Strong) AND ≥ 2 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM1, PM4, PM5, PM6, PP1_Moderate, PP3_Moderate)

1 Very Strong (PVS1, PS2_Very Strong, PS4_Very Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM1, PM4, PM5, PM6, PP1_Moderate, PP3_Moderate) AND 1 Supporting (PVS1_Supporting, PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3)

1 Very Strong (PVS1, PS2_Very Strong, PS4_Very Strong) AND ≥ 2 Supporting (PVS1_Supporting, PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3)

≥ 2 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM5_Strong, PM6_Strong, PP1_Strong, PP3_Strong)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM5_Strong, PM6_Strong, PP1_Strong, PP3_Strong) AND ≥ 3 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM1, PM4, PM5, PM6, PP1_Moderate, PP3_Moderate)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM5_Strong, PM6_Strong, PP1_Strong, PP3_Strong) AND 2 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM1, PM4, PM5, PM6, PP1_Moderate, PP3_Moderate) AND ≥ 2 Supporting (PVS1_Supporting, PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM5_Strong, PM6_Strong, PP1_Strong, PP3_Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM1, PM4, PM5, PM6, PP1_Moderate, PP3_Moderate) AND ≥ 4 Supporting (PVS1_Supporting, PS2_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3)

Likely Pathogenic

1 Very Strong (PVS1, PS2_Very Strong, PS4_Very Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM1, PM4, PM5, PM6, PP1_Moderate, PP3_Moderate)

Benign

≥ 2 Strong (BS1, BS2)

1 Stand Alone (BA1)

Likely Benign

1 Strong (BS1, BS2) AND 1 Supporting (BP2, BP3, BP5, BP7)

≥ 2 Supporting (BP2, BP3, BP5, BP7)

Files & Images

PVS1 Decision Tree:

Combining Rules:

PM1 Table:

Paralogous Gene Table:

PS1_Variants impacting splicing: