ClinVar Miner

Submissions for variant NM_000334.4(SCN4A):c.4387C>A (p.Arg1463Ser)

gnomAD frequency: 0.00003  dbSNP: rs774453167
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000810571 SCV000950784 likely pathogenic Familial hyperkalemic periodic paralysis 2023-08-10 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 1463 of the SCN4A protein (p.Arg1463Ser). This variant is present in population databases (rs774453167, gnomAD 0.004%). This missense change has been observed in individuals with myotonia (PMID: 29605429). ClinVar contains an entry for this variant (Variation ID: 654578). 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. Experimental studies have shown that this missense change affects SCN4A function (PMID: 29605429). This variant disrupts the p.Arg1463 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been observed in individuals with SCN4A-related conditions (PMID: 29606556; Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx RCV001568013 SCV001791802 likely pathogenic not provided 2019-01-02 criteria provided, single submitter clinical testing Reported in a case control study of sudden infant death syndrome. Functional expression studies showed impaired fast inactivation of R1463S compared to wild type, resulting in a gain of function effect on sodium channel function (Mannikko et al., 2018).; Not observed at a significant frequency 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: 31043699, 29605429, 29605428)

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