Submissions for variant NM_000335.5(SCN5A):c.2894G>A (p.Arg965His)

dbSNP: rs199473181

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455768	SCV000540290	uncertain significance	not specified	2016-10-20	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in <5 probands, functional study shows reduced activity when coexpressed w/ WT channel. Possible segregation in PMID 22373669, but details are not provided.
Color Diagnostics, LLC DBA Color Health	RCV001842319	SCV001352007	uncertain significance	Cardiac arrhythmia	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 965 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). A functional study using transfected HEK293 cells has shown that this variant causes a reduction in peak current density (PMID: 24573164). This variant has been reported in two individuals affected with Brugada syndrome (PMID: 16764707, 20129283) and in an individual affected with arrhythmia (PMID: 22373669). This variant has been identified in 1/245418 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	RCV003764736	SCV002948542	uncertain significance	not provided	2024-01-05	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 965 of the SCN5A protein (p.Arg965His). 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: 16764707, 30403391). ClinVar contains an entry for this variant (Variation ID: 67764). 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: 24573164). 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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058534	SCV000090054	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:16764707;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.