ClinVar Miner

Submissions for variant NM_001160160.2(SCN5A):c.4900G>A (p.Val1634Ile) (rs199473293)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523560 SCV000617273 uncertain significance not provided 2017-08-21 criteria provided, single submitter clinical testing The V1667I variant of uncertain significance in the SCN5A gene has been reported previously in association with arrhythmia (Piippo et al., 2001; Maekawa et al., 2005; Kapplinger et al., 2010; Hekkala et al., 2010). Initially, Piippo et al. (2001) reported V1667I in a Finnish individual with LQTS. Although this variant was identified in 8 additional family members, who on average had significantly longer QT intervals than family members who did not harbor the variant, only two of these family members also had a diagnosis of prolonged QT interval (Piippo et al., 2001). Subsequently, Maekawa et al. (2005) identified the V1667I variant in an individual with ventricular tachycardia who harbored a second variant in SCN5A and Kapplinger et al. (2010) identified the V1667I variant in an individual with suspected Brugada syndrome. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V1667I 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 in the transmembrane helical domain of the S5 region of repeat IV. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, the V1667I variant lacks sufficient evidence, including observation in a significant number of affected individuals, segregation studies, and functional characterization, that would further clarify its potential pathogenicity.
Color Health, Inc RCV001190160 SCV001357586 uncertain significance Arrhythmia 2018-12-20 criteria provided, single submitter clinical testing
Invitae RCV001345002 SCV001539097 uncertain significance Brugada syndrome 2020-10-12 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 1667 of the SCN5A protein (p.Val1667Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with long QT syndrome and Brugada syndrome (PMID: 11274952, 19843921). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67949). 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 RCV000058734 SCV000090254 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:11274952;PMID:15840476). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Medical Research Institute,Tokyo Medical and Dental University RCV000190217 SCV000222068 likely pathogenic Long QT syndrome no assertion criteria provided research

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