Submissions for variant NM_000335.5(SCN5A):c.5767G>A (p.Ala1923Thr)

gnomAD frequency: 0.00003  dbSNP: rs137854603

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000420298	SCV000514559	uncertain significance	not provided	2024-04-22	criteria provided, single submitter	clinical testing	Observed in several individuals with Brugada syndrome in the published literature (PMID: 10690282, 12106943, 11807557, 19251209, 20129283, 21273195, 31231243); Several published in vitro functional studies suggest that p.(A1924T) impacts channel function; nevertheless, it is unclear how these studies may translate to a pathogenic role in vivo (PMID: 10690282, 19171938, 23104914); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25758664, 15795161, 16472137, 11893549, 27262167, 19171938, 12106943, 25904541, 33306788, 23104914, 17993328, 11673053, 19251209, 20129283, 21273195, 11807557, 11420310, 11123251, 12393785, 19027780, 14753626, 21454796, 10690282, 9950665, 14961552, 11410597, 10940383, 12639704, 23414114, 31231243, 30662450, 21167176, 16505387, 30203441, 35650162, 36007333, 26111534, 33131149, 36435694, 35753512)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000420298	SCV000637191	likely benign	not provided	2025-01-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000009978	SCV000916016	likely pathogenic	Brugada syndrome 1	2018-12-10	criteria provided, single submitter	clinical testing	The SCN5A c.5770G>A (p.Ala1924Thr) missense variant has described in four studies and found in a heterozygous state in a total of three individuals affected with Brugada syndrome and in a homozygous state in a pair of identical twins affected with sinus node dysfunction (Rook et al. 1999; Meregalli et al. 2009; Amin et al. 2011; Chiang et al. 2015). The p.Ala1924Thr variant was present in one of 1400 controls (Kapplinger et al. 2010) and is reported at a frequency of 0.001084 in the Ashkenazi Jewish population of the Genome Aggregation Database. Functional studies in Xenopus oocytes demonstrated that the variant significantly affected the inward sodium current causing an increase during the action potential upstroke (Rook et al. 1999). Tan et al. (200) demonstrated that the p.Ala1924Thr increased the rate of fast activation of the sodium channel whilst inhibiting the slow activation induced by the calcium-dependent binding of calmodulin. Based on the evidence, the p.Ala1924Thr variant is classified as likely pathogenic for Brugada syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Color Diagnostics, LLC DBA Color Health	RCV001841233	SCV001347318	uncertain significance	Cardiac arrhythmia	2023-02-22	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1924 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant affects sodium channel activation and inactivation properties (PMID: 10690282, 11807557, 23104914) and reduces binding affinity for calmodulin (PMID: 16505387). This variant has been reported in an individual affected with Brugada syndrome (PMID: 10690282), in homozygous identical twins with sinus node dysfunction and atrial tachycardia (PMID: 26111534), as well as in a control individual (PMID: 25904541). This variant has been identified in 16/280642 chromosomes (12/10352 Ashkenazi Jewish chromosomes, 0.11%) in the general population by the Genome Aggregation Database (gnomAD). In summary, although this variant has been reported in multiple affected individuals, this variant also occurs at an appreciable frequency in the general population. 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.
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	RCV002251424	SCV002522176	uncertain significance	Long QT syndrome; Brugada syndrome	2021-08-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004017231	SCV004849285	uncertain significance	Cardiovascular phenotype	2019-02-19	criteria provided, single submitter	clinical testing	The c.5770G>A (p.A1924T) alteration is located in exon 28 (coding exon 27) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 5770, causing the alanine (A) at amino acid position 1924 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
OMIM	RCV000009978	SCV000030199	pathogenic	Brugada syndrome 1	1999-12-01	no assertion criteria provided	literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058806	SCV000090326	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:10690282;PMID:12106943;PMID:19251209;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.