Submissions for variant NM_000335.5(SCN5A):c.3010T>C (p.Cys1004Arg)

gnomAD frequency: 0.00029  dbSNP: rs199473183

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155885	SCV000205596	uncertain significance	not specified	2013-08-11	criteria provided, single submitter	clinical testing	The Cys1004Arg variant in SCN5A has been reported in 1 individual with Long QT s yndrome and was not identified in 2600 control chromosomes (Kapplinger 2009). Da ta from large population studies is insufficient to assess the frequency of this variant. This variant has been reported in dbSNP without frequency information (rs199473183). Computational analyses (biochemical amino acid properties, conser vation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or aga inst an impact to the protein. Additional information is needed to fully assess the clinical significance of this variant.
GeneDx	RCV000766795	SCV000235430	uncertain significance	not provided	2017-03-31	criteria provided, single submitter	clinical testing	The C1004R variant of uncertain significance in the SCN5A gene has been previously identified in one individual referred for LQTS genetic testing (Kapplinger et al., 2009; Kapplinger et al., 2015). In addition, Jamuar et al. (2016) reported this variant as an incidental finding in an Asian Indian patient undergoing genomic sequencing; however, the clinical phenotype of this individual is unclear. The C1004R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Moreover, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, the C1004R variant has been observed in 70/30526 (0.22%) alleles from individuals of South Asian background, including one homozygous individual in large population cohorts (Lek et al., 2016). Based on review of the data in the context of the 2015 ACMG standards and guidelines for the interpretation of sequence variants (Richards et al., 2015), we now interpret C1004R as a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV001842325	SCV000913667	likely benign	Cardiac arrhythmia	2018-10-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000766795	SCV001016975	likely benign	not provided	2023-12-14	criteria provided, single submitter	clinical testing
Mendelics	RCV000987213	SCV001136462	uncertain significance	Brugada syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001145176	SCV001305823	likely benign	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001145177	SCV001305824	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	RCV001145178	SCV001305825	benign	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV000987213	SCV001305826	benign	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001149459	SCV001310415	benign	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001149460	SCV001310416	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.
Ambry Genetics	RCV002433565	SCV002753299	benign	Cardiovascular phenotype	2022-07-08	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Revvity Omics, Revvity	RCV000766795	SCV003821334	uncertain significance	not provided	2022-09-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000766795	SCV004154188	uncertain significance	not provided	2023-05-01	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000987213	SCV005061008	uncertain significance	Brugada syndrome 1		criteria provided, single submitter	clinical testing	The observed missense variant c.3010T>C (p.Cys1004Arg) in SCN5A gene has been reported previously in 1 individual affected with SCN5A-related disorder (Kapplinger et al. 2009). The p.Cys1004Arg variant is reported with an allele frequency of 0.03% in the gnomAD exomes database. This variant has been submitted to the ClinVar database as Benign / Likely Benign / Uncertain Significance. The amino acid change p.Cys1004Arg in SCN5A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Cys at position 1004 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS).
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058543	SCV000090063	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:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.