Submissions for variant NM_000335.5(SCN5A):c.3343C>T (p.Arg1115Trp)

gnomAD frequency: 0.00006  dbSNP: rs199473196

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000058567	SCV000637132	uncertain significance	not provided	2024-11-11	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 1116 of the SCN5A protein (p.Arg1116Trp). This variant is present in population databases (rs199473196, gnomAD 0.009%). 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: 67793). 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.
Ambry Genetics	RCV000618999	SCV000737862	uncertain significance	Cardiovascular phenotype	2022-07-08	criteria provided, single submitter	clinical testing	The c.3346C>T (p.R1116W) alteration is located in exon 18 (coding exon 17) of the SCN5A gene. This alteration results from a C to T substitution at nucleotide position 3346, causing the arginine (R) at amino acid position 1116 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Athena Diagnostics	RCV000058567	SCV000843714	uncertain significance	not provided	2018-08-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001842335	SCV001736606	uncertain significance	Cardiac arrhythmia	2023-03-07	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 1116 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 reported in two ostensibly healthy individuals (PMID: 20129283). This variant has also been identified in 6/268350 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.
GeneDx	RCV000058567	SCV001773190	uncertain significance	not provided	2022-12-09	criteria provided, single submitter	clinical testing	Reported in at least two individuals from a control cohort (Kapa et al., 2009); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20129283, 19841300, 22581653, 26746457)
Fulgent Genetics, Fulgent Genetics	RCV002490657	SCV002789719	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	2021-08-25	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001842335	SCV004833610	uncertain significance	Cardiac arrhythmia	2024-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 1116 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 reported in two ostensibly healthy individuals (PMID: 20129283). This variant has also been identified in 6/268350 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586531	SCV005075883	uncertain significance	not specified	2024-04-02	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.3346C>T (p.Arg1116Trp) results in a non-conservative amino acid change located in the Sodium ion transport-associated domain (IPR010526) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.1e-05 in 236978 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3346C>T in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 67793). Based on the evidence outlined above, the variant was classified as uncertain significance.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058567	SCV000090087	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:19841300;PMID:20129283).