Submissions for variant NM_000335.5(SCN5A):c.6013C>G (p.Pro2005Ala)

gnomAD frequency: 0.00109  dbSNP: rs45489199

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154829	SCV000204511	likely benign	not specified	2015-10-01	criteria provided, single submitter	clinical testing	p.Pro2006Ala in exon 28 of SCN5A: This variant is not expected to have clinical significance because it has been identified in 0.2% (124/63230) of European chr omosomes and 0.23% (15/6614) of Finnish chromosomes by the Exome Aggregation Con sortium (ExAC, http://exac.broadinstitute.org; dbSNP rs45489199). Additionally, proline (Pro) at position 2006 is not conserved in mammals or evolutionarily dis tant species and this variant has been identified in at least 5 mammals. Please note, this variant has been reported in the literature in 4 individuals with lon g QT, 5 individuals with VF, 2 cases of SIDS (Priori 2000, Ackerman 2004, Arnest ad 2007, Krahn 2009, Skinner 2011, Shinlapawittayatorn 2011, Novotny 2011). Stud ies have shown that the p.Pro2006Ala variant exhibits increased persistent sodiu m currents in whole-cell voltage clamp measurements (Wang 2007, Shinlapawittayat orn 2011), but behaves like wild type when expressed with the p.His558Arg varian t (Shinlapawittayatorn 2011). However, these in vitro assays may not accurately represent biological function.
Blueprint Genetics	RCV000154829	SCV000207239	likely benign	not specified	2015-11-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000058824	SCV000235311	likely benign	not provided	2020-10-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22378279, 22360817, 21215473, 19597050, 26749013, 20875080, 2107088, 23714088, 27153395, 28988457, 10961955, 23631430, 23465283, 21070882, 17210839, 17210841, 15851227, 21410720, 21109022, 26159999, 23571586, 20129283, 29032884, 28831623, 28807990, 28798025, 16712702, 16379539, 19841300, 25351510, 26746457, 28301460, 29728395, 29672598, 30762279, 31337358, 31043699, 32880476)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000058824	SCV000291828	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000242689	SCV000319172	likely benign	Cardiovascular phenotype	2018-10-26	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.
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000678920	SCV000805127	uncertain significance	Brugada syndrome 1	2017-11-27	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000058824	SCV000884485	likely benign	not provided	2020-03-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001842403	SCV000911069	likely benign	Cardiac arrhythmia	2018-04-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154829	SCV000918200	likely benign	not specified	2020-12-07	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.6016C>G (p.Pro2006Ala) 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 0.0011 in 229592control chromosomes (gnomAD and publication data), including 1 homozygote. The observed variant frequency is approximately 54-fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Long QT Syndrome phenotype (2.1e-05), strongly suggesting that the variant is benign. The variant, c.6016C>G, has been reported in the literature in individuals affected with Long QT Syndrome and sudden death, but was also detected in controls (Aziz_2013, Christiansen_2014, Kapa_2009, Krahn_2009, Marcondes_2017). This variant has been reported not associate with any ECG characteristics in one large cohort, but associate with cardiac arrest and VF in another large cohort (Paludan-Muller_2019). These reports do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. Functional studies have shown the Pro2006Ala variant to exhibit increased persistent sodium currents in whole-cell voltage clamp measurements (Wang_2007, Shinlapawittayatorn_2011). Interestingly, when two variants, P2006A and a common polymorphism H558R, were expressed on the same allele, the cells displayed currents that behaved like wild type (Shinlapawittayatorn_2011). Therefore the biological significance of these in vitro studies is unclear. In fact, a case-control study showed that individuals with the variant of interest did not have significantly different QTc interval times compared to non-variant carriers (Ghouse_2015). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign/likely benign n=9, VUS n=3). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000058824	SCV001153852	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	SCN5A: BS2
Illumina Laboratory Services, Illumina	RCV001149898	SCV001310897	benign	Sick sinus syndrome 1	2018-03-23	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	RCV000678920	SCV001310898	benign	Brugada syndrome 1	2018-03-23	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	RCV001149899	SCV001310899	likely benign	Dilated cardiomyopathy 1E	2018-03-23	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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001149900	SCV001310900	likely benign	Progressive familial heart block, type 1A	2018-03-23	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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001149901	SCV001310901	uncertain significance	Ventricular fibrillation, paroxysmal familial, type 1	2018-03-23	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	RCV001149902	SCV001310902	uncertain significance	Long QT syndrome 3	2018-03-23	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149714	SCV003838875	benign	Cardiomyopathy	2021-09-02	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058824	SCV000090344	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:10961955;PMID:15851227;PMID:16379539;PMID:16712702;PMID:17210839;PMID:19841300;PMID:19597050;PMID:21109022;PMID:21410720;PMID:21070882;PMID:20129283).
PreventionGenetics, part of Exact Sciences	RCV004542729	SCV004769246	likely benign	SCN5A-related disorder	2020-09-08	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).