ClinVar Miner

Submissions for variant NM_000334.4(SCN4A):c.4609G>A (p.Gly1537Ser)

gnomAD frequency: 0.00006  dbSNP: rs571210585
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000551049 SCV000658584 uncertain significance Hyperkalemic periodic paralysis 2025-01-06 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1537 of the SCN4A protein (p.Gly1537Ser). This variant is present in population databases (rs571210585, gnomAD 0.01%). This missense change has been observed in individual(s) with essential tremor and epilepsy (PMID: 26427606). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 222028). 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 SCN4A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SCN4A function (PMID: 26427606). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics RCV005003560 SCV000895123 uncertain significance Potassium-aggravated myotonia; Paramyotonia congenita of Von Eulenburg; Hypokalemic periodic paralysis, type 2; Hyperkalemic periodic paralysis; Congenital myasthenic syndrome 16; Congenital myopathy 22A, classic; Congenital myopathy 22B, severe fetal 2024-05-07 criteria provided, single submitter clinical testing
GeneDx RCV000207488 SCV001988962 uncertain significance not provided 2020-10-13 criteria provided, single submitter clinical testing Reported in 4 family members with tremor, 2 of whom also had seizures (Bergareche et al., 2015); Published functional studies demonstrate a damaging effect on channel function (Bergareche et al., 2015); This variant is associated with the following publications: (PMID: 26427606)
Revvity Omics, Revvity RCV000207488 SCV003818681 uncertain significance not provided 2022-08-10 criteria provided, single submitter clinical testing
OMIM RCV000207488 SCV000262821 uncertain significance not provided 2024-07-16 no assertion criteria provided literature only
PreventionGenetics, part of Exact Sciences RCV004530250 SCV004120231 uncertain significance SCN4A-related disorder 2024-09-20 no assertion criteria provided clinical testing The SCN4A c.4609G>A variant is predicted to result in the amino acid substitution p.Gly1537Ser. This variant has been reported to segregate in five family members with tremors or tremors with seizures (Bergareche et al. 2015. PubMed ID: 26427606). However, this variant is also reported in 0.0093% (20/281418) of alleles in individuals of European (non-Finnish) descent in gnomAD and may be too common for an autosomal dominant variant. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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