ClinVar Miner

Submissions for variant NM_000334.4(SCN4A):c.2023C>T (p.Arg675Trp)

gnomAD frequency: 0.00001  dbSNP: rs121908556
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000713092 SCV000843660 pathogenic not provided 2016-06-08 criteria provided, single submitter clinical testing
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München RCV001254163 SCV001430119 pathogenic Paramyotonia congenita of Von Eulenburg 2020-07-01 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000713092 SCV001500144 pathogenic not provided 2020-10-01 criteria provided, single submitter clinical testing
Invitae RCV000206954 SCV001588729 pathogenic Hyperkalemic periodic paralysis 2023-12-18 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 675 of the SCN4A protein (p.Arg675Trp). This variant is present in population databases (rs121908556, gnomAD 0.003%). This missense change has been observed in individuals with autosomal dominant SCN4A-related conditions (PMID: 15596759, 29606556). ClinVar contains an entry for this variant (Variation ID: 5902). 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%. Experimental studies have shown that this missense change affects SCN4A function (PMID: 19052238). This variant disrupts the p.Arg675 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15596759, 19052238, 22926674). 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 RCV000713092 SCV002019137 likely pathogenic not provided 2020-03-21 criteria provided, single submitter clinical testing
GeneDx RCV000713092 SCV002599598 likely pathogenic not provided 2023-02-06 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Different missense changes at this residue (R675G) and (R675Q) have been reported in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 31708864, 19201608, 19052238, 29606556, 22016737, 32962503, 24772081, 20301669, 29930533, 22926674, 15596759)
OMIM RCV000006263 SCV000026445 pathogenic Normokalemic periodic paralysis, potassium-sensitive 2004-12-14 no assertion criteria provided literature only
GeneReviews RCV000206954 SCV000262568 not provided Hyperkalemic periodic paralysis no assertion provided literature only

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