Submissions for variant NM_000335.5(SCN5A):c.1598G>A (p.Arg533His)

gnomAD frequency: 0.00009  dbSNP: rs146848219

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182980	SCV000235379	uncertain significance	not provided	2020-08-26	criteria provided, single submitter	clinical testing	Reported in a patient with Brugada syndrome in an abstract presented at a Heart Rhythm Society meeting (Tan et al., 2012); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID#180512; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25904541)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000182980	SCV000260085	uncertain significance	not provided	2024-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 533 of the SCN5A protein (p.Arg533His). This variant is present in population databases (rs146848219, gnomAD 0.03%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 37652022). ClinVar contains an entry for this variant (Variation ID: 180512). 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 disruptive. 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	RCV000269424	SCV000444139	uncertain significance	Paroxysmal familial ventricular fibrillation	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000308105	SCV000444140	uncertain significance	Dilated Cardiomyopathy, Dominant	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000365101	SCV000444141	uncertain significance	Long QT syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000272892	SCV000444142	uncertain significance	Congenital long QT syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000157479	SCV000444143	uncertain significance	Brugada syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000388106	SCV000444144	uncertain significance	Sick sinus syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000277355	SCV000444145	uncertain significance	Progressive familial heart block	2016-06-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000619790	SCV000737253	likely benign	Cardiovascular phenotype	2021-09-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV001842500	SCV001360095	uncertain significance	Cardiac arrhythmia	2023-04-07	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 533 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 not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has been identified in 16/278974 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	RCV002478471	SCV002789614	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	2021-10-16	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000182980	SCV003821332	uncertain significance	not provided	2019-11-14	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149961	SCV003838222	uncertain significance	Cardiomyopathy	2021-11-29	criteria provided, single submitter	clinical testing
New York Genome Center	RCV003227681	SCV003925181	uncertain significance	Dilated cardiomyopathy 1E	2022-06-24	criteria provided, single submitter	clinical testing	The c.1598G>A variant has not previously been reported in affected individuals and it has been deposited in ClinVar [ClinVar ID: 180512] as Variant of Uncertain Significance by multiple submitters. The c.1598G>A variant is observed in 51 alleles (0.0086% minor allele frequency with 0 homozygotes) in population databases(gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8). This variant has been reported in 3 control individuals (out of 8,975 individuals) and has not been detected in a cohort of Brugada syndrome and long QT cases (PMID: 25904541). The c.1598G>A variant is located in exon 12 of this 28-exon gene and is predicted to replace an evolutionarily conserved arginine amino acid with histidine at position 533 in the interdomain linker of DI/DII region in the encoded protein [PMID: 30364184]. In silico predictions are in favor of damaging effect for p.(Arg533His) variant [(CADD v1.6 = 23.1, REVEL = 0.662)]; however, there are no functional studies to support or refute these predictions. Two different missense variants p.(Arg533Ser) and p.(Arg533Cys) affecting the same amino acid have been reported in ClinVar [ClinVar ID:918769and 575108] as a Variant of Uncertain Significance with arrhythmia phenotype. Based on available evidence this c.1598G>A p.(Arg533His) variant identified in SCN5A is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV001842500	SCV004833739	uncertain significance	Cardiac arrhythmia	2024-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 533 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 not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has been identified in 16/278974 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.
Blueprint Genetics	RCV000157479	SCV000207224	uncertain significance	Brugada syndrome	2014-10-14	no assertion criteria provided	clinical testing