Submissions for variant NM_001040142.2(SCN2A):c.4976C>T (p.Ala1659Val)

dbSNP: rs1060503101

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463674	SCV000551884	pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2022-08-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 410984). This missense change has been observed in individual(s) with clinical features of early infantile epileptic encephalopathy (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1659 of the SCN2A protein (p.Ala1659Val).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268119	SCV001446779	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	RCV001530194	SCV001739486	likely pathogenic	Seizures, benign familial infantile, 3	2020-02-28	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV003313957	SCV004013800	likely pathogenic	Developmental and epileptic encephalopathy, 11		criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000410984). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003313957	SCV005087098	pathogenic	Developmental and epileptic encephalopathy, 11	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Variants causing a gain of function result in developmental and epileptic encephalopathy 11 (MIM#613721) or benign familial infantile seizures 3 (MIM#607745), whereas variants causing loss of function result in autism spectrum disorder and/or intellectual disability, with or without childhood-onset seizures (OMIM, PMID: 29691040, PMID: 31904126). 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Ion transport domain (DECIPHER). (I) 801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with developmental and epileptic encephalopathy (ClinVar, PMID: 35365919). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV001003339	SCV001156233	pathogenic	Seizure	2020-02-03	no assertion criteria provided	clinical testing	20% mosacism