ClinVar Miner

Submissions for variant NM_000334.4(SCN4A):c.4427T>C (p.Met1476Thr)

dbSNP: rs1064795409
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484396 SCV000571185 likely pathogenic not provided 2020-01-27 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27060299, 32660787)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000484396 SCV000610051 likely pathogenic not provided 2017-06-28 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001061560 SCV001226307 pathogenic Hyperkalemic periodic paralysis 2024-01-02 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1476 of the SCN4A protein (p.Met1476Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with paramyotonia congenita (PMID: 27060299, 32660787). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 421864). 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 SCN4A protein function with a positive predictive value of 95%. This variant disrupts the p.Met1476 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17998485, 22250216). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000484396 SCV002019133 likely pathogenic not provided 2021-05-26 criteria provided, single submitter clinical testing

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