Submissions for variant NM_000335.5(SCN5A):c.568C>T (p.Arg190Trp)

dbSNP: rs199473068

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001545009	SCV000954040	uncertain significance	not provided	2024-09-14	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 190 of the SCN5A protein (p.Arg190Trp). This variant is present in population databases (rs199473068, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 657115). 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	RCV001841992	SCV001359261	uncertain significance	Cardiac arrhythmia	2022-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 190 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/242820 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196953	SCV001367587	uncertain significance	Sick sinus syndrome 1	2020-03-05	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3.
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV001258364	SCV001435333	uncertain significance	Brugada syndrome 1	2020-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV001545009	SCV001764248	uncertain significance	not provided	2025-02-10	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
AiLife Diagnostics, AiLife Diagnostics	RCV001545009	SCV002502933	uncertain significance	not provided	2021-11-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002345853	SCV002653323	uncertain significance	Cardiovascular phenotype	2020-12-04	criteria provided, single submitter	clinical testing	The p.R190W variant (also known as c.568C>T), located in coding exon 4 of the SCN5A gene, results from a C to T substitution at nucleotide position 568. The arginine at codon 190 is replaced by tryptophan, an amino acid with dissimilar properties, and is located in the DI-S2/S3 region of the protein.. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV001841992	SCV004827330	uncertain significance	Cardiac arrhythmia	2023-11-30	criteria provided, single submitter	clinical testing