ClinVar Miner

Submissions for variant NM_000334.4(SCN4A):c.2704G>A (p.Gly902Ser) (rs200517944)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000764142 SCV000895127 uncertain significance Hypokalemic periodic paralysis 1; Potassium aggravated myotonia; Paramyotonia congenita of von Eulenburg; Hypokalemic periodic paralysis, type 2; Hyperkalemic Periodic Paralysis Type 1; Congenital myasthenic syndrome, acetazolamide-responsive 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000654656 SCV000776552 uncertain significance Hyperkalemic Periodic Paralysis Type 1 2017-11-15 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 902 of the SCN4A protein (p.Gly902Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs200517944, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with SCN4A-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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