ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.2944T>C (p.Cys982Arg) (rs199473182)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000151788 SCV000200240 uncertain significance not specified 2019-03-07 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Cys982Arg variant in SCN5A has been previously reported in 1 individual with sudden death (Hofman-Bang, 2006) and in 0.077% of African chromosomes in gnomAD (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). Uncertain significance in ClinVar. In summary, the clinical significance of the p.Cys982Arg variant is uncertain.
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 RCV001084383 SCV000545092 likely benign Brugada syndrome 2020-12-02 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845398 SCV000987462 uncertain significance Primary familial dilated cardiomyopathy criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852549 SCV000995248 uncertain significance Sudden cardiac arrest 2019-03-15 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001145287 SCV001305940 uncertain significance Dilated cardiomyopathy 1E 2019-03-20 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001149576 SCV001310536 uncertain significance Progressive familial heart block, type 1A 2019-03-20 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001149577 SCV001310537 uncertain significance Brugada syndrome 1 2019-03-20 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001149578 SCV001310538 uncertain significance Long QT syndrome 3 2019-03-20 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001149579 SCV001310539 uncertain significance Paroxysmal familial ventricular fibrillation 1 2019-03-20 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001149580 SCV001310540 benign Sick sinus syndrome 1, autosomal recessive 2019-03-20 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Color Health, Inc RCV001182243 SCV001347630 likely benign Arrhythmia 2019-10-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285552 SCV001472007 uncertain significance none provided 2020-07-21 criteria provided, single submitter clinical testing The SCN5A c.2944T>C, p.Cys982Arg variant (rs199473182), has been reported in multiple individuals selected for cardiac arrhythmia (Hofman-Bang 2006), sudden cardiac death (Cann 2017), or actionable variants in genomic medicine studies (Amendola 2015 and Dorschner 2013). This variant has been submitted to the ClinVar database (Variation ID: 67769). It is found in the African population with an allele frequency of 0.08% (18/23,286 alleles) in the Genome Aggregation Database. The cysteine at codon 982 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Cys982Arg variant is uncertain at this time. References: Amendola et al. Actionable Exomic Incidental Findings in 6503 Participants: Challenges of Variant Classification. Genome Res. 2015 Mar. Cann et al. Phenotype-driven Molecular Autopsy for Sudden Cardiac Death. Clin Genet. 2017 Jan. Dorschner et al. Actionable, Pathogenic Incidental Findings in 1,000 Participants' Exomes. Am J Hum Genet. 2013 Oct 3. Hofman-Bang et al. High-efficiency Multiplex Capillary Electrophoresis Single Strand Conformation Polymorphism (multi-CE-SSCP) Mutation Screening of SCN5A: A Rapid Genetic Approach to Cardiac Arrhythmia. Clin Genet. 2006 Jun. Gene statement: Pathogenic germline variants in the SCN5A gene are inherited in an autosomal dominant manner and are associated with dilated cardiomyopathy 1E (MIM: 601154), familial atrial fibrillation 10 (MIM: 614022), Brugada syndrome 1 (MIM: 601144), nonprogressive heart block and progressive heart block 1A (MIM: 113900), Long QT syndrome-3 (MIM: 603830), familial ventricular fibrillation (MIM: 603829), and, more rarely, autosomal recessive sick sinus syndrome-1 (MIM: 608567).
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.
CSER _CC_NCGL, University of Washington RCV000058539 SCV000190595 uncertain significance Sudden cardiac death 2014-06-01 no assertion criteria provided research

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