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 2020-08-19 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25370050, 16414944, 21126620, 29728395, 22581653, 31865383, 28087622)
Ambry Genetics RCV000618126 SCV000736250 uncertain significance Cardiovascular phenotype 2016-04-26 criteria provided, single submitter clinical testing The p.R1913H variant (also known as c.5738G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at nucleotide position 5738. The arginine at codon 1913 is replaced by histidine, an amino acid with highly similar properties. This variant was previously reported in a long QT syndrome cohort and a Brugada syndrome cohort; however, clinical details were limited (Napolitano C et al.JAMA.2005;294(23):2975-80;HermidaJS et al.AmJCardiol.2010;106(12):1758-62).This variant was previously reported in the SNPDatabase as rs199473327. Based on data from ExAC, the A allele has an overall frequency of approximately <0.01% (4/105586). This variant was not reported in population-based cohorts in the following databases: NHLBIExomeSequencing Project (ESP)and 1000 Genomes Project. In the ESP, this variant was not observed in6337samples (12674alleles) with coverage at this position.This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis.Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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 2020-09-02 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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