ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1537C>T (p.Arg513Cys) (rs145733679)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621309 SCV000737812 uncertain significance Cardiovascular phenotype 2016-11-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000182976 SCV000235375 uncertain significance not provided 2013-10-11 criteria provided, single submitter clinical testing p.Arg513Cys (CGT>TGT): c.1537 C>T in exon 12 of the SCN5A gene (NM_198056.2) The Arg513Cys variant in the SCN5A gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Arg513Cys results in a non-conservative amino acid substitution of a positively charged Arginine with a neutral, polar Cysteine at a position that is not conserved across species. In silico analysis was inconsistent with regard to the effect this variant may have on the protein structure/function. Mutations in nearby residues (Thr512Ile, Gly514Cys, Arg523Cys) have been reported in association with cardiac conduction disease and arrhythmia, supporting the functional importance of this region of the protein. The 1000 Genomes database identified the Arg513Cys variant with a frequency of 0.2%, 1/492 alleles, in individuals of African ancestry. However, Arg513Cys was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. With the clinical and molecular information available at this time, we cannot definitively determine if Arg513Cys is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s).
Invitae RCV000814854 SCV000955286 uncertain significance Brugada syndrome 2018-09-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 513 of the SCN5A protein (p.Arg513Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs145733679, ExAC 0.02%). This variant has been observed in individuals affected with hypertrophic cardiomyopathy or third degree atrioventricular block (III AVB) (PMID: 27554632, 28878402). ClinVar contains an entry for this variant (Variation ID: 201456). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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