ClinVar Miner

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

gnomAD frequency: 0.00002  dbSNP: rs199473596
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
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.
Invitae RCV003541163 SCV001496368 uncertain significance not provided 2023-08-31 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. 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 19632629). 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. ClinVar contains an entry for this variant (Variation ID: 67804). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 19632629, 28341781, 31918855).
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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.