ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.6013C>G (p.Pro2005Ala) (rs45489199)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare 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 RCV000154829 SCV000235311 likely benign not specified 2017-10-18 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV001083666 SCV000291828 likely benign Brugada syndrome 2020-12-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV000242689 SCV000319172 likely benign Cardiovascular phenotype 2018-10-26 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
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 RCV001282399 SCV000884485 likely benign none provided 2020-03-20 criteria provided, single submitter clinical testing
Color Health, Inc RCV000776128 SCV000911069 likely benign 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 Praxis fuer Humangenetik Tuebingen RCV000058824 SCV001153852 uncertain significance not provided 2018-09-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001149898 SCV001310897 benign Sick sinus syndrome 1, autosomal recessive 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 Clinical Services Laboratory,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 Clinical Services Laboratory,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 Clinical Services Laboratory,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 Clinical Services Laboratory,Illumina RCV001149901 SCV001310901 uncertain significance Paroxysmal familial ventricular fibrillation 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 Clinical Services Laboratory,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.
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).

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