ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.5291T>A (p.Phe1764Tyr)

gnomAD frequency: 0.00001  dbSNP: rs796053037
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188998 SCV000242629 likely pathogenic not provided 2023-05-24 criteria provided, single submitter clinical testing Identified in at least one individual in a cohort of individuals with epilepsy and neurodevelopmental disorders in published literature (Lindy et al., 2018); This substitution is predicted to be within the transmembrane segment S6 of the fourth homologous domain; The majority of missense variants in this gene are considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29655203)
Invitae RCV001065456 SCV001230414 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2024-01-10 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine, which is neutral and non-polar, with tyrosine, which is neutral and polar, at codon 1764 of the SCN1A protein (p.Phe1764Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant developmental and epileptic encephalopathy (PMID: 29655203; Invitae). ClinVar contains an entry for this variant (Variation ID: 206863). 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 SCN1A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Center for Personalized Medicine, Children's Hospital Los Angeles RCV003156083 SCV003845321 likely pathogenic See cases 2022-12-21 criteria provided, single submitter clinical testing

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