ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.2962C>T (p.Arg988Trp)

gnomAD frequency: 0.00004  dbSNP: rs768691853
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183019 SCV000235427 uncertain significance not provided 2022-10-31 criteria provided, single submitter clinical testing Identified in a patient with Brugada syndrome, but it is unknown whether this individual was screened for variants in other genes associated with Brugada syndrome (Sommariva et al., 2013); Identified in a patient with dilated cardiomyopathy who also harbored a variant in the RBM20 gene (Lu et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30662450, 23321620, 30165862)
Invitae RCV000183019 SCV000545089 uncertain significance not provided 2024-01-15 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 988 of the SCN5A protein (p.Arg988Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Brugada syndrome and/or dilated cardiomyopathy (PMID: 23321620, 30165862). ClinVar contains an entry for this variant (Variation ID: 201486). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Color Diagnostics, LLC DBA Color Health RCV001842911 SCV001348293 uncertain significance Cardiac arrhythmia 2023-01-27 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 988 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two unrelated individuals affected with Brugada syndrome (PMID: 23321620, 32268277) and in an individual with dilated cardiomyopathy (PMID: 30165862). This variant has been identified in 5/238498 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics RCV002492815 SCV002779419 uncertain significance Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10 2021-11-15 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV001842911 SCV004815194 uncertain significance Cardiac arrhythmia 2023-12-01 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 988 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two unrelated individuals affected with Brugada syndrome (PMID: 23321620, 32268277) and in an individual with dilated cardiomyopathy (PMID: 30165862). This variant has been identified in 5/238498 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Clinical Genetics, Academic Medical Center RCV000183019 SCV001925480 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000183019 SCV001973642 uncertain significance not provided no assertion criteria provided clinical testing

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