ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.5333C>T (p.Thr1778Met) (rs199473634)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183115 SCV000235525 uncertain significance not specified 2017-04-24 criteria provided, single submitter clinical testing A variant of uncertain significance has also been identified in the SCN5A gene. The T1779M variant has been previous reported in multiple individuals with varying phenotypes, including LQTS, Brugada syndrome, and HCM (Tester et al., 2005; Kapplinger et al., 2009; Kapplinger et al., 2010; Lopes et al., 2015). However, in these published cases, no segregation data is available to further clarify the role of this variant in disease. Nevertheless, this variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server; Kapplinger et al., 2015). The T1779M 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. Furthermore, 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. However, whole-cell patch clamp studies in HEK293 cells suggest that SCN5A channels harboring this variant have wild-type function (Kapplinger et al., 2015). Additionally, this variant is also classified in ClinVar as a variant of uncertain significance by a different clinical laboratory (ClinVar SCV000545029.1; Landrum et al., 2016).
Invitae RCV000469805 SCV000545029 uncertain significance Brugada syndrome 2019-11-08 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1779 of the SCN5A protein (p.Thr1779Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs199473634, ExAC 0.006%). This variant has been observed in individuals affected with long QT syndrome (PMID: 27566755, 19841300) and dilated cardiomyopathy (PMID: 28416588). Additionally, this variant has been observed in several individuals referred for long QT syndrome or Brugada syndrome testing (PMID: 15840476, 19716085, 20129283). ClinVar contains an entry for this variant (Variation ID: 67985). Experimental studies have shown that this missense change does not have a significant effect on SCN5A activity (PMID: 25904541). 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.
Ambry Genetics RCV000617171 SCV000738199 uncertain significance Cardiovascular phenotype 2017-10-17 criteria provided, single submitter clinical testing Insufficient evidence
Illumina Clinical Services Laboratory,Illumina RCV001146112 SCV001306832 uncertain significance Dilated cardiomyopathy 1E 2019-08-02 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 Clinical Services Laboratory,Illumina RCV001146113 SCV001306833 uncertain significance Progressive familial heart block, type 1A 2019-08-02 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 Clinical Services Laboratory,Illumina RCV001146114 SCV001306834 likely benign Sick sinus syndrome 1, autosomal recessive 2019-08-02 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 Clinical Services Laboratory,Illumina RCV001146115 SCV001306835 uncertain significance Brugada syndrome 1 2019-08-02 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 Clinical Services Laboratory,Illumina RCV001146116 SCV001306836 uncertain significance Long QT syndrome 3 2019-08-02 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 Clinical Services Laboratory,Illumina RCV001146117 SCV001306837 uncertain significance Paroxysmal familial ventricular fibrillation 1 2019-08-02 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.
Integrated Genetics/Laboratory Corporation of America RCV000183115 SCV001337777 uncertain significance not specified 2020-01-13 criteria provided, single submitter clinical testing Variant summary: SCN5A c.5336C>T (p.Thr1779Met) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 303096 control chromosomes (gnomAD and publications). The observed variant frequency is approximately 1.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Cardiomyopathy phenotype (2.5e-05), suggesting that the variant is benign. c.5336C>T has been reported in the literature in individuals affected with long QT syndrome, dilated cardiomyopathy and Brugada syndrome (ie. Tester_2005, Kapplinger_2009, Kapa_2009, Stavropoulos_2016, Dal Ferro_2017). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. At least one functional study reports this variant has no impact on protein function (Kapplinger_2016). Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Color RCV001184483 SCV001350459 uncertain significance Arrhythmia 2019-06-13 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058771 SCV000090291 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:15840476;PMID:19716085;PMID:19841300;PMID:22378279). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
CSER _CC_NCGL, University of Washington RCV000148849 SCV000190592 uncertain significance Long QT syndrome 2014-06-01 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786219 SCV000924953 uncertain significance not provided 2017-04-05 no assertion criteria provided provider interpretation

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