Submissions for variant NM_000335.5(SCN5A):c.892G>A (p.Gly298Ser)

gnomAD frequency: 0.00004  dbSNP: rs137854608

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151803	SCV000200266	uncertain significance	not specified	2014-12-29	criteria provided, single submitter	clinical testing	The p.Gly298Ser variant in SCN5A has been reported in 1 Mexican individual with atrioventricular conduction block (Wang 2002), and has been identified by our la b in 1 Indian child with DCM. This variant has been identified in 2/11578 Latino chromosomes and in 1/8724 East Asian chromosomes by the Exome Aggregation Conso rtium (ExAC, http://exac.broadinstitute.org; dbSNP rs137854608). In vitro functi onal studies provide some evidence that the p.Gly298Ser variant may impact prote in function (Wang 2002, Saito 2009). However, these types of assays may not accu rately represent biological function. Additional computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In s ummary, the clinical significance of the p.Gly298Ser variant is uncertain.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415287	SCV000492554	uncertain significance	Primary dilated cardiomyopathy; Migraine; Hemiplegia	2014-11-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003137510	SCV000930944	uncertain significance	not provided	2023-11-09	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 298 of the SCN5A protein (p.Gly298Ser). This variant is present in population databases (rs137854608, gnomAD 0.01%). This missense change has been observed in individual(s) with atrioventricular conduction block and dilated cardiomyopathy (PMID: 11804990, 19056759, 31983221). ClinVar contains an entry for this variant (Variation ID: 9387). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 11804990, 19056759). 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.
Illumina Laboratory Services, Illumina	RCV000009985	SCV001309965	uncertain significance	Progressive familial heart block, type 1A	2017-04-27	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001149035	SCV001309966	uncertain significance	Sick sinus syndrome 1	2017-04-27	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	RCV001149036	SCV001309967	uncertain significance	Dilated cardiomyopathy 1E	2017-04-27	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	RCV001149037	SCV001309968	uncertain significance	Brugada syndrome 1	2017-04-27	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	RCV001149038	SCV001309969	uncertain significance	Long QT syndrome 3	2017-04-27	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	RCV001149039	SCV001309970	uncertain significance	Ventricular fibrillation, paroxysmal familial, type 1	2017-04-27	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	RCV001841235	SCV001350253	uncertain significance	Cardiac arrhythmia	2022-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 298 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). Functional studies have shown that this variant decreases sodium channel current density and activation kinetics (PMID: 11804990, 19056759). However, clinical relevance of this observation is not clear. This variant has been reported in individuals affected with atrioventricular conduction block (PMID: 11804990) and irritable bowel syndrome (PMID: 19056759). This variant has also been identified in 7/280252 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.
Fulgent Genetics, Fulgent Genetics	RCV002482852	SCV002787484	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	2022-02-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003137510	SCV003821329	uncertain significance	not provided	2020-03-20	criteria provided, single submitter	clinical testing
GeneDx	RCV003137510	SCV003842931	uncertain significance	not provided	2022-12-07	criteria provided, single submitter	clinical testing	Identified in a patient with second-degree heart block diagnosed in childood that progressed to third-degree AV block (Wang et al., 2002); Identified in a patient with DCM in published literature (Mazzarotto et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies suggest a damaging effect (Wang et al., 2002); however, it is unclear whether these findings recapitulate in vivo conditions; This variant is associated with the following publications: (PMID: 25871451, 17854786, 17111025, 20176021, 25898860, 26401487, 22581653, 23105938, 22323988, 16540748, 19027780, 17504259, 31983221, 11804990, 24535448, 19056759)
All of Us Research Program, National Institutes of Health	RCV001841235	SCV004823251	uncertain significance	Cardiac arrhythmia	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 298 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). Functional studies have shown that this variant decreases sodium channel current density and activation kinetics (PMID: 11804990, 19056759). However, clinical relevance of this observation is not clear. This variant has been reported in individuals affected with atrioventricular conduction block (PMID: 11804990) and irritable bowel syndrome (PMID: 19056759). This variant has also been identified in 7/280252 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	RCV004018612	SCV004944542	uncertain significance	Cardiovascular phenotype	2021-08-16	criteria provided, single submitter	clinical testing	The c.892G>A (p.G298S) alteration is located in exon 7 (coding exon 6) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 892, causing the glycine (G) at amino acid position 298 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV003137510	SCV005041939	uncertain significance	not provided	2024-04-01	criteria provided, single submitter	clinical testing	SCN5A: PM2, PS4:Moderate, PS3:Supporting
OMIM	RCV000009985	SCV000030206	pathogenic	Progressive familial heart block, type 1A	2002-01-22	no assertion criteria provided	literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058858	SCV000090378	not provided	Atrioventricular block		no assertion provided	literature only	This variant has been reported as associated with Atrioventricular conduction block in the following publications (PMID:11804990;PMID:19056759). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.