ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.2944T>C (p.Cys982Arg) (rs199473182)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER_CC_NCGL; University of Washington Medical Center RCV000058539 SCV000190595 uncertain significance Sudden cardiac death 2014-06-01 no assertion criteria provided research
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058539 SCV000090059 not provided Sudden cardiac death no assertion provided literature only This variant has been reported as associated with Sudden adult death syndrome in the following publications (PMID:16712702). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724184 SCV000226704 uncertain significance not provided 2014-08-01 criteria provided, single submitter clinical testing
GeneDx RCV000724184 SCV000235424 uncertain significance not provided 2018-04-27 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN5A gene. The C982R variant has previously been reported in association with HCM and sudden death (Hofman-Bang et al., 2006; Adabag et al., 2010; Lopes et al., 2015; Cann et al., 2016). This variant has also been observed, both independently and in conjunction with additional cardiogenetic variants, in multiple other unrelated individuals referred for cardiac genetic testing at GeneDx. Thus far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. This variant has been observed in 18/23122 (0.08%) alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016). The C982R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
Invitae RCV000470981 SCV000545092 uncertain significance Brugada syndrome 2018-04-06 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 982 of the SCN5A protein (p.Cys982Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is present in population databases (rs199473182, ExAC 0.06%). This variant has been reported in several individual cases of sudden unexplained death (PMID: 16712702, 20102864, 27000522). This variant has also been reported in an individual with arrhythmia (PMID: 26746457). ClinVar contains an entry for this variant (Variation ID: 67769). 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 arginine 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 RCV000151788 SCV000200240 uncertain significance not specified 2014-09-29 criteria provided, single submitter clinical testing The Cys982Arg variant in SCN5A has been previously reported in 1 individual with sudden death (Hofman-Bang, 2006) and in 2/8280 European American chromosomes an d 3/3888 African American chromosomes by the NHLBI Exome Sequencing Project (htt p://; dbSNP rs199473182). This variant is located in a domain that is believed to be enriched in variants that are present in controls although this does not rule out a pathogenic role (Kapa 2009). In summary, the clinical significance of the Cys982Arg variant is uncertain.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845398 SCV000987462 uncertain significance Familial dilated cardiomyopathy criteria provided, single submitter clinical testing

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