Submissions for variant NM_000335.5(SCN5A):c.6007T>C (p.Phe2003Leu)

gnomAD frequency: 0.00192  dbSNP: rs41311117

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171818	SCV000050838	benign	Long QT syndrome; Brugada syndrome	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041636	SCV000065332	likely benign	not specified	2012-03-19	criteria provided, single submitter	clinical testing	Phe2004Leu in exon 28 of SCN5A: This variant is not expected to have clinical si gnificance because it has been identified in 0.3% (21/6776) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs41311117). Phe2004Leu in exon 28 of SCN5A (rs41311117; allele frequency = 0.3%, 21/6776) **
Eurofins Ntd Llc (ga)	RCV000041636	SCV000228662	likely benign	not specified	2014-10-17	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000202785	SCV000257780	likely benign	Brugada syndrome 1; Long QT syndrome 3	2015-05-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000058821	SCV000259928	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000058821	SCV000280965	likely benign	not provided	2015-06-19	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Ambry Genetics	RCV000251940	SCV000318496	likely benign	Cardiovascular phenotype	2022-03-30	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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000041636	SCV000747931	uncertain significance	not specified	2017-02-23	criteria provided, single submitter	clinical testing
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000678922	SCV000805129	uncertain significance	Brugada syndrome 1	2017-12-07	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000058821	SCV000843727	likely benign	not provided	2018-04-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001841618	SCV000910859	likely benign	Cardiac arrhythmia	2018-03-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000041636	SCV000920195	likely benign	not specified	2020-12-07	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.6010T>C (p.Phe2004Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 213020 control chromosomes. The observed variant frequency is approximately 21- fold the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is benign. c.6010T>C has been reported in the literature in individuals affected with sudden death, cardiomyopathies, Long-QT syndrome, and myocarditis (examples: Arnestead_2007, Belkaya_2017, Petrikin_2018, Marcondes_2018, Raju_2019, Mahdieh_2020), but also in healthy controls (examples: Kapplinger_2010, Ghouse_2017). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. At least one publication reports experimental evidence indicating that the variant could affect SCN5A function (example: Wang_2007), however a large Danish population study did not identify an association between this variant and cardiac conditions (Ghouse_2017). 12 other ClinVar submitters (evaluation after 2014) cited the variant as uncertain significance (n=4) and benign/ likely benign (n=8). Based on the evidence outlined above, the variant was classified as likely benign.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852960	SCV000995709	likely benign	Cardiomyopathy	2019-01-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000058821	SCV001153853	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	SCN5A: BP4
Illumina Laboratory Services, Illumina	RCV001145574	SCV001306262	uncertain significance	Dilated cardiomyopathy 1E	2018-03-20	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	RCV000678922	SCV001306263	uncertain significance	Brugada syndrome 1	2018-03-20	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	RCV001145575	SCV001306264	benign	Sick sinus syndrome 1	2018-03-20	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	RCV001145687	SCV001306380	uncertain significance	Progressive familial heart block, type 1A	2018-03-20	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	RCV001145688	SCV001306381	uncertain significance	Long QT syndrome 3	2018-03-20	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	RCV001145689	SCV001306382	uncertain significance	Ventricular fibrillation, paroxysmal familial, type 1	2018-03-20	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.
GeneDx	RCV000058821	SCV001795222	likely benign	not provided	2021-05-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 33131149, 31737537, 31043699, 31337358, 29672598, 29728395, 28359509, 27711072, 18456723, 17605181, 15851227, 20129283, 23414114, 23465283, 17210841, 22685113)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000058821	SCV003799423	likely benign	not provided	2022-12-20	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000852960	SCV003838876	benign	Cardiomyopathy	2021-09-03	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058821	SCV000090341	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:15851227;PMID:17210839;PMID:18071069;PMID:18456723;PMID:19841300;PMID:17605181;PMID:20129283).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000058821	SCV001744811	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000058821	SCV001930655	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000058821	SCV001960030	likely benign	not provided		no assertion criteria provided	clinical testing