ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.5738G>A (p.Arg1913His) (rs199473327)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183104 SCV000235514 uncertain significance not provided 2015-12-01 criteria provided, single submitter clinical testing The R1913H variant has been reported previously in association with LQTS and Brugada syndrome and was absent in 800 control chromosomes, however, specific clinical and family history information was not provided (Napolitano et al., 2005; Hermida et al., 2010. The R1913H variant was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although the R1913H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (S1904L, Q1909R) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), supporting the functional importance of this region of the protein. Nevertheless, additional evidence is needed to determine whether this variant is pathogenic or benign.
Ambry Genetics RCV000618126 SCV000736250 uncertain significance Cardiovascular phenotype 2016-04-26 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Fulgent Genetics,Fulgent Genetics RCV000765732 SCV000897100 uncertain significance Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1, autosomal recessive; Progressive familial heart block, type 1A; Paroxysmal familial ventricular fibrillation 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV001202604 SCV001373721 uncertain significance Brugada syndrome 2019-09-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1913 of the SCN5A protein (p.Arg1913His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs199473327, ExAC 0.03%). This variant has been observed in individuals with clinical features of SCN5A-related conditions, but has also been observed in at least one unaffected family member (PMID: 16414944, 21126620). ClinVar contains an entry for this variant (Variation ID: 68009). 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.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058804 SCV000090324 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:16414944). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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