Submissions for variant NM_000335.5(SCN5A):c.1895C>T (p.Thr632Met)

gnomAD frequency: 0.00001  dbSNP: rs199473134

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001842302	SCV002051981	uncertain significance	Cardiac arrhythmia	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 632 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that the mutant channel has no significantly different sodium current densities compared to the control channel (PMID: 24573164). This variant has been reported in two individuals with suspected Brugada syndrome (PMID: 20129283). This variant has been identified in 3/244512 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	RCV003430657	SCV002160722	uncertain significance	not provided	2023-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 632 of the SCN5A protein (p.Thr632Met). 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 Brugada syndrome (PMID: 20129283, 25904541). ClinVar contains an entry for this variant (Variation ID: 67695). 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 does not substantially affect 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.
Fulgent Genetics, Fulgent Genetics	RCV002477196	SCV002793240	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	2021-11-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003430657	SCV004154190	uncertain significance	not provided	2023-08-01	criteria provided, single submitter	clinical testing	SCN5A: PM2
All of Us Research Program, National Institutes of Health	RCV001842302	SCV004832298	uncertain significance	Cardiac arrhythmia	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 632 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that the mutant channel has no significantly different sodium current densities compared to the control channel (PMID: 24573164). This variant has been reported in two individuals with suspected Brugada syndrome (PMID: 20129283). This variant has been identified in 3/244512 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.
Ambry Genetics	RCV004019040	SCV004943821	uncertain significance	Cardiovascular phenotype	2020-07-21	criteria provided, single submitter	clinical testing	The c.1895C>T (p.T632M) alteration is located in exon 13 (coding exon 12) of the SCN5A gene. This alteration results from a C to T substitution at nucleotide position 1895, causing the threonine (T) at amino acid position 632 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058459	SCV000089979	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.