ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.674G>A (p.Arg225Gln) (rs199473071)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058836 SCV000090356 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:16922724). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Invitae RCV000812561 SCV000952879 uncertain significance Brugada syndrome 2018-09-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 225 of the SCN5A protein (p.Arg225Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs199473071, ExAC 0.04%). This variant has been observed in individuals affected with long QT syndrome, dilated cardiomyopathy, or sudden death (PMID: 16922724, 28779003, 29247119). ClinVar contains an entry for this variant (Variation ID: 68033). Experimental studies have shown that this missense change results in a protein with mildly altered electrophysiological properties (PMID: 24815523, 28779003). 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. This variant disrupts the p.Arg225 amino acid residue in SCN5A. Other variants that disrupt this residue have been observed in affected individuals (PMID: 20031634, 12574143, 24815523), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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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