Submissions for variant NM_000335.5(SCN5A):c.6001G>A (p.Ala2001Thr)

gnomAD frequency: 0.00006  dbSNP: rs771018427

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000219261	SCV000272418	uncertain significance	not specified	2015-03-04	criteria provided, single submitter	clinical testing	The p.Ala2002Thr variant in SCN5A has not been previously reported in individual s with cardiomyopathy or in large population studies. Alanine (Ala) at position 2002 is not conserved in mammals or evolutionarily distant species and 1 mammal (pika) carries a threonine (Thr) at this position, raising the possibility that this change may be tolerated. Additional computational prediction tools also sug gest that the p.Ala2002Thr variant may not impact the protein, though this infor mation is not predictive enough to rule out pathogenicity. In summary, the clini cal significance of the p.Ala2002Thr variant is uncertain.
GeneDx	RCV000766281	SCV000536631	uncertain significance	not provided	2025-02-19	criteria provided, single submitter	clinical testing	Identified in a cohort of individuals with Brugada syndrome (PMID: 33221895); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33221895)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000766281	SCV000820224	uncertain significance	not provided	2024-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2002 of the SCN5A protein (p.Ala2002Thr). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of Brugada syndrome (PMID: 33221895). ClinVar contains an entry for this variant (Variation ID: 229236). 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 tolerated. 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.
Color Diagnostics, LLC DBA Color Health	RCV001842985	SCV001354113	uncertain significance	Cardiac arrhythmia	2023-03-20	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 2002 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one individual affected with Brugada syndrome (PMID: 33221895). This variant has been identified in 6/195482 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	RCV002354612	SCV002657583	uncertain significance	Cardiovascular phenotype	2024-07-23	criteria provided, single submitter	clinical testing	The p.A2002T variant (also known as c.6004G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at nucleotide position 6004. The alanine at codon 2002 is replaced by threonine, an amino acid with similar properties. This variant has been detected in a cohort of patients with Brugada syndrome or related features; however, clinical details were limited (Ciconte G et al. Eur Heart J. 2021 Mar;42(11):1082-1090). This amino acid position is not well conserved in available vertebrate species, and threonine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002500715	SCV002790008	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	2024-04-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000219261	SCV004122487	uncertain significance	not specified	2023-10-31	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.6004G>A (p.Ala2002Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.1e-05 in 195482 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6004G>A has been reported in the literature in at least one individual affected with Brugada syndrome (e.g., Ciconte_2021). This report does not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 33221895). Six submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV001842985	SCV004814498	uncertain significance	Cardiac arrhythmia	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 2002 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one individual affected with Brugada syndrome (PMID: 33221895). This variant has been identified in 6/195482 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.