ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.1261G>A (p.Val421Met) (rs781507889)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413776 SCV000491398 likely pathogenic not provided 2016-01-11 criteria provided, single submitter clinical testing The V421M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a conserved position in the transmembrane helical segment S3 in the first homologous domain, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Multiple missense variants in nearby residues have been reported in Human Gene Mutation Database in association with SCN1A-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, the V421M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Baylor Genetics RCV001328664 SCV001519832 likely pathogenic Severe myoclonic epilepsy in infancy 2019-10-30 criteria provided, single submitter clinical testing This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
PerkinElmer Genomics RCV000413776 SCV002020001 pathogenic not provided 2019-05-20 no assertion criteria provided clinical testing

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