Submissions for variant NM_000335.5(SCN5A):c.3581G>A (p.Arg1194His)

gnomAD frequency: 0.00002  dbSNP: rs199473596

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001842339	SCV001348998	uncertain significance	Cardiac arrhythmia	2023-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1195 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An in-vitro functional study using transfected HEK293 cells has shown that this variant caused normal peak and late current but abnormal voltage-dependent gating parameters (PMID: 19632629). This variant has been reported in an individual affected with Brugada syndrome (PMID: 28341781) and in an individual affected with left ventricular non-compaction cardiomyopathy (PMID: 31918855). This variant has also been reported in a child affected with QT prolongation, fever-induced ventricular arrhythmias and sudden death (PMID: 19632629). This child was compound heterozygous for this missense variant and a pathogenic truncation variant. The child's heterozygous parents were asymptomatic and showed normal electrocardiogram. This variant has been identified in 6/241892 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003541163	SCV001496368	uncertain significance	not provided	2024-07-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1195 of the SCN5A protein (p.Arg1195His). 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 clinical features of SCN5A-related conditions (PMID: 19632629, 28341781, 31918855). ClinVar contains an entry for this variant (Variation ID: 67804). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 19632629). 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.
Fulgent Genetics, Fulgent Genetics	RCV002490658	SCV002781828	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	2021-09-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001842339	SCV004824944	uncertain significance	Cardiac arrhythmia	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1195 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An in-vitro functional study using transfected HEK293 cells has shown that this variant caused normal peak and late current but abnormal voltage-dependent gating parameters (PMID: 19632629). This variant has been reported in an individual affected with Brugada syndrome (PMID: 28341781) and in an individual affected with left ventricular non-compaction cardiomyopathy (PMID: 31918855). This variant has also been reported in a child affected with QT prolongation, fever-induced ventricular arrhythmias and sudden death (PMID: 19632629). This child was compound heterozygous for this missense variant and a pathogenic truncation variant. The child's heterozygous parents were asymptomatic and showed normal electrocardiogram. This variant has been identified in 6/241892 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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058579	SCV000090099	not provided	Ventricular tachycardia		no assertion provided	literature only	This variant has been reported as associated with Ventricular tachycardia in the following publications (PMID:19632629). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.