ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.1264G>A (p.Val422Met)

dbSNP: rs886042528
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000725185 SCV000334735 likely pathogenic not provided 2015-09-09 criteria provided, single submitter clinical testing
Baylor Genetics RCV000314247 SCV000807295 likely pathogenic Severe myoclonic epilepsy in infancy criteria provided, single submitter clinical testing
GeneDx RCV000725185 SCV001822952 pathogenic not provided 2020-02-03 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This substitution is predicted to be in the cytoplasmic loop between first and second homologous domains; Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 31864146, 29056246, 22848613, 25326635, 24776920, 17347258, 23891399)
Labcorp Genetics (formerly Invitae), Labcorp RCV005090344 SCV005834339 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2024-10-27 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 422 of the SCN1A protein (p.Val422Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dravet syndrome (PMID: 22848613, 29056246). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 282973). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
PreventionGenetics, part of Exact Sciences RCV004543016 SCV004771920 likely pathogenic SCN1A-related disorder 2023-12-15 no assertion criteria provided clinical testing The SCN1A c.1264G>A variant is predicted to result in the amino acid substitution p.Val422Met. This variant has been reported in two individuals with infantile epilepsy or Dravet syndrome (Kwong et al. 2012. PubMed ID: 22848613; Butler et al. 2017. PubMed ID: 29056246), and in Kwong et al. the variant was determined to be de novo. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. This variant resides on the cytoplasmic side of the S6 segment in a region where disease-associated variants are common (affected residues include 418, 419, 420, 421, and 422; see, HGMD). A gene-specific machine learning-based model for clinical prediction indicates this variant is pathogenic with 93% likelihood (Heyne et al. 2020. PubMed ID 32801145). This variant is interpreted as likely pathogenic.

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