Submissions for variant NM_000335.5(SCN5A):c.3553G>A (p.Ala1185Thr)

gnomAD frequency: 0.00001  dbSNP: rs199473595

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156315	SCV000206033	uncertain significance	not specified	2015-03-12	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Ala1186Thr va riant in SCN5A has been identified in 1 Japanese individual with AV Block and a family history of LQTS (Horigome 2010) and in 1 Asian adult with HCM, who carrie d a pathogenic variant in a different HCM gene (LMM unpublished data). This vari ant has also been identified in 2/5990 East Asian chromosomes by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs199473595). Ala nine (Ala) at position 1186 is not conserved in mammals or evolutionarily distan t species. One mammal (tenrec) has a threonine (Thr) at this position, raising t he possibility that this change may be tolerated. Additional computational predi ction tools suggest that this variant may not impact the protein, though this in formation is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Ala1186Thr variant is uncertain, collectively this data suggests that it is more likely to be benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003654192	SCV000760217	uncertain significance	not provided	2023-12-30	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 1186 of the SCN5A protein (p.Ala1186Thr). This variant is present in population databases (rs199473595, gnomAD 0.03%). This missense change has been observed in individual(s) with personal and/or family history of arrhythmias and Brugada syndrome (PMID: 15996170, 19996378, 26743238, 29202755). ClinVar contains an entry for this variant (Variation ID: 67802). 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.
Fulgent Genetics, Fulgent Genetics	RCV000765735	SCV000897103	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	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001150963	SCV001312059	uncertain significance	Brugada syndrome 1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001150964	SCV001312060	uncertain significance	Dilated cardiomyopathy 1E	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001150965	SCV001312061	uncertain significance	Long QT syndrome 3	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001150966	SCV001312062	uncertain significance	Progressive familial heart block, type 1A	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001150967	SCV001312063	uncertain significance	Ventricular fibrillation, paroxysmal familial, type 1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001150968	SCV001312064	uncertain significance	Sick sinus syndrome 1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Diagnostics, LLC DBA Color Health	RCV001842338	SCV001352597	uncertain significance	Cardiac arrhythmia	2023-03-20	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1186 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with long QT syndrome (PMID: 19996378, 26632536, 28472724) and in an individual affected with arrhythmia (PMID: 26743238). It has also been reported in an individual affected with Brugada syndrome (PMID: 29202755), in an individual affected with dilated cardiomyopathy (PMID: 31983221), in an individual affected with restrictive cardiomyopathy (PMID: 30165862), as well as in a healthy control individual (PMID: 15996170). This variant has been identified in 4/237884 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.
All of Us Research Program, National Institutes of Health	RCV001842338	SCV004818654	uncertain significance	Cardiac arrhythmia	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1186 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with long QT syndrome (PMID: 19996378, 26632536, 28472724) and in an individual affected with arrhythmia (PMID: 26743238). It has also been reported in an individual affected with Brugada syndrome (PMID: 29202755), in an individual affected with dilated cardiomyopathy (PMID: 31983221), in an individual affected with restrictive cardiomyopathy (PMID: 30165862), as well as in a healthy control individual (PMID: 15996170). This variant has been identified in 4/237884 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	RCV000058576	SCV000090096	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19996378). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.