Submissions for variant NM_000335.5(SCN5A):c.3781G>A (p.Gly1261Ser)

gnomAD frequency: 0.00001  dbSNP: rs137854616

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001753410	SCV000825694	uncertain significance	not provided	2023-07-28	criteria provided, single submitter	clinical testing	Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 32533946) indicates that this missense variant is expected to disrupt SCN5A function. Experimental studies have shown that this missense change affects SCN5A function (PMID: 32533946). 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. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1262 of the SCN5A protein (p.Gly1262Ser). This variant is present in population databases (rs137854616, gnomAD 0.01%). This missense change has been observed in individual(s) with Brugada syndrome and/or dilated cardiomyopathy or hypertrophic cardiomyopathy and Brugada syndrome (PMID: 15338453, 20129283, 27554632, 30193851). ClinVar contains an entry for this variant (Variation ID: 9399).
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000755698	SCV000883130	uncertain significance	Long QT syndrome 3	2018-11-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV004528100	SCV000916019	uncertain significance	SCN5A-related disorder	2017-04-28	criteria provided, single submitter	clinical testing	The SCN5A c.3784G>A (p.Gly1262Ser) missense variant has been reported in two studies in which it is found in a total of seven individuals in a heterozygous state, including in one proband with Brugada syndrome, the proband's affected brother and as yet two unaffected children, in one additional unrelated individual with Brugada syndrome, in one individual diagnosed with dilated cardiomyopathy, and in one individual diagnosed with hypertrophic cardiomyopathy (Shin et al. 2004; Priganc et al. 2016). The p.Gly1262Ser variant was absent from 352 control chromosomes, but is reported at a frequency of 0.00013 in the South Asian population of the Genome Aggregation Database. Based on the evidence, the p.Gly1262Ser variant is classified as a variant of uncertain significance but suspicious for pathogenicity for SCN5A-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Laboratory Services, Illumina	RCV001146725	SCV001307479	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	RCV001146726	SCV001307480	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	RCV000755698	SCV001307481	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	RCV001146727	SCV001307482	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.
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000010001	SCV001422293	likely pathogenic	Brugada syndrome 1	2020-02-21	criteria provided, single submitter	clinical testing
GeneDx	RCV001753410	SCV001985375	uncertain significance	not provided	2019-11-27	criteria provided, single submitter	clinical testing	Reported in individuals with DCM and HCM (Priganc et al., 2016), an individual referred for Brugada syndrome testing (Kapplinger et al., 2010), and a child with noncompaction cardiomyopathy (van Waning et al., 2018); Reported in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar Variant ID#9399; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32048431, 31677787, 24903439, 19336922, 22581653, 18436145, 19027780, 15338453, 27554632, 29447731, 30662450, 20129283, 24136861, 31019283, 30193851, 31737537, 32533946, 33131149)
All of Us Research Program, National Institutes of Health	RCV003996086	SCV004831376	uncertain significance	Cardiac arrhythmia	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 1262 of the SCN5A protein. This variant is also known as c.3781G>A (p.Gly1261Ser) based on a different transcript NM_000335.5. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with Brugada syndrome including two who were from the same family (PMID: 15338453, 20129283), two individuals affected with dilated cardiomyopathy and one individual with hypertrophic cardiomyopathy (PMID: 27554632), and in another individual affected with noncompaction cardiomyopathy and atrial fibrillation (Van Waning 2020, dissertation, Erasmus University Rotterdam). This variant has been identified in 8/282850 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	RCV004018613	SCV004943834	uncertain significance	Cardiovascular phenotype	2022-04-07	criteria provided, single submitter	clinical testing	The c.3784G>A (p.G1262S) alteration is located in exon 21 (coding exon 20) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 3784, causing the glycine (G) at amino acid position 1262 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
OMIM	RCV000010001	SCV000030222	pathogenic	Brugada syndrome 1	2004-01-01	no assertion criteria provided	literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058602	SCV000090122	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:15338453;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.