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

gnomAD frequency: 0.00004  dbSNP: rs768691853

Total submissions: 7

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)
Labcorp Genetics (formerly Invitae), Labcorp	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