Submissions for variant NM_001040142.2(SCN2A):c.5317G>A (p.Ala1773Thr)

dbSNP: rs796053162

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel, Clingen	RCV002319456	SCV005061659	pathogenic	Complex neurodevelopmental disorder	2023-05-09	reviewed by expert panel	curation	The c.5317G>A (NM_001040142.2) variant in SCN2A is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 1773 (p.Ala1773Thr). This variant has been reported in 9 probands with complex neurodevelopmental disorder (PMIDs: 34758253, 33000761, 28947817, 29655203, 31440721, 31785789, 34469436, 32400968, 35431799), including as a de novo occurrence with confirmed parental relationships in 2 individual(s) (PMIDs: 31785789, 32400968) and as a de novo occurrence with assumed parental relationships in 2 individuals PMID: 33000761, 35431799). This variant is absent from gnomAD v2.1.1. Whole-cell patch-clamp recordings of voltage-gated Na+ currents in HEK293T cell in showed a significant hyperpolarizing shift in the voltage dependence of the activation curve and a depolarizing shift of steady-state fast inactivation accompanied by decreased current density indicating that this variant impacts protein function (PMIDs: 32400968, 32400968). This variant resides within a region of SCN2A that is defined as a mutational hotspot and/or critical functional domain by the ClinGen Epilepsy Sodium Channel VCEP (PM1). In summary, this variant meets the criteria to be classified as pathogenic for complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS3, PS4, PS2, PM1, PM2_Supporting. (Epilepsy Sodium Channel VCEP specifications v1.0; approved 5/9/23).
GeneDx	RCV000189176	SCV000242808	pathogenic	not provided	2023-03-02	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that the variant results in a loss of function effect on the protein (Miao et al., 2020); This substitution is predicted to be within the transmembrane segment S6 of the fourth homologous domain; Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28256214, 34469436, 34758253, 29655203, 24267886, 20196795, 23849776, 32400968, 33000761, 31785789, 31440721, 35431799, 27824329, 28379373, 24077912)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524506	SCV000551877	pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2024-02-23	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1773 of the SCN2A protein (p.Ala1773Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of developmental and epileptic encephalopathy (PMID: 32400968; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207024). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN2A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SCN2A function (PMID: 32400968). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000622944	SCV000741215	likely pathogenic	Inborn genetic diseases	2015-12-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000189176	SCV001152490	likely pathogenic	not provided	2019-03-01	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001250742	SCV001426159	likely pathogenic	Developmental and epileptic encephalopathy, 11	2018-05-14	criteria provided, single submitter	clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV001250742	SCV001438071	pathogenic	Developmental and epileptic encephalopathy, 11		criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV001250742	SCV002012289	pathogenic	Developmental and epileptic encephalopathy, 11	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (PMID: 34469436, 28947817, PS1). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Ala1773Val) has been reported as pathogenic (PMID:28379373, PM5). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94, 3Cnet: 0.996, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genomics England Pilot Project, Genomics England	RCV001250742	SCV001760061	likely pathogenic	Developmental and epileptic encephalopathy, 11		no assertion criteria provided	clinical testing
Neurology Department, Shenzhen Children's Hospital	RCV001847844	SCV002099475	pathogenic	West syndrome	2022-02-16	no assertion criteria provided	clinical testing
Channelopathy-Associated Epilepsy Research Center	RCV002319456	SCV002605509	not provided	Complex neurodevelopmental disorder		no assertion provided	literature only