ClinVar Miner

Submissions for variant NM_000334.4(SCN4A):c.4776G>A (p.Met1592Ile)

dbSNP: rs886041805
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489768 SCV000577698 likely pathogenic not provided 2015-07-02 criteria provided, single submitter clinical testing The M1592I variant in the SCN4A gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The M1592I variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M1592I variant is a conservative amino acid substitution that occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant at the same residue (M1592V) has been reported in the Human Gene Mutation Database in association with hyperkalemic periodic paralysis and another nearby missense variant (V1598M) has been reported in association with myotonia (Stenson et al., 2014), supporting the functional importance of this region of the protein. The M1592I variant is a strong candidate for a disease-causing variant
Fulgent Genetics, Fulgent Genetics RCV000763017 SCV000893468 likely pathogenic Hypokalemic periodic paralysis, type 1; Potassium-aggravated myotonia; Paramyotonia congenita of Von Eulenburg; Hypokalemic periodic paralysis, type 2; Familial hyperkalemic periodic paralysis; Congenital myasthenic syndrome 16 2018-10-31 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001856911 SCV002249222 pathogenic Familial hyperkalemic periodic paralysis 2022-08-22 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met1592 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1659668, 8242056, 9131651, 18046642, 21665479, 23801527, 24714718, 24943082). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 427072). This missense change has been observed in individual(s) with clinical features of autosomal dominant SCN4A-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1592 of the SCN4A protein (p.Met1592Ile).

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