ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1538G>A (p.Arg513His) (rs397517951)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000687410 SCV000814974 uncertain significance Brugada syndrome 2018-05-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 513 of the SCN5A protein (p.Arg513His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with sudden unexplained nocturnal death syndrome (PMID: 24529773) and an individual with dilated cardiomyopathy (PMID: 27554632). ClinVar contains an entry for this variant (Variation ID: 48285). 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 histidine 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. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000041600 SCV000065296 likely benign not specified 2012-09-28 criteria provided, single submitter clinical testing Arg513His in exon 12 of SCN5A: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including primates and o ther mammals. Of note, all other primates (chimp, gorilla, orangutan, and others ) have a histidine (His) at this position despite high nearby amino acid conserv ation. A disease modifying role of this variant cannot be excluded.

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