ClinVar Miner

Submissions for variant NM_024334.2(TMEM43):c.1073C>T (p.Ser358Leu) (rs63750743)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621202 SCV000736856 pathogenic Cardiovascular phenotype 2017-06-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Strong segregation with disease (lod >3 = >10 meioses)
Blueprint Genetics RCV000039375 SCV000207271 pathogenic Arrhythmogenic right ventricular cardiomyopathy 2015-10-15 criteria provided, single submitter clinical testing
GeneDx RCV000183944 SCV000236436 pathogenic not provided 2018-08-05 criteria provided, single submitter clinical testing The Ser358Leu mutation in the TMEM43 gene has been reported in association with ARVC (McNally E et al., 2009). In the Newfoundland population, Merner N et al. identified a founder mutation, Ser358Leu, in the TMEM43 gene, and classified the disorder as autosomal dominant arrhythmogenic right ventricular cardiomyopathy type 5 (Merner N et al., 2008; McNally E et al., 2009). Based on a study of 83 individuals with ARVC5, the Ser358Leu mutation appears to be fully penetrant and associated with a severe phenotype.
Heart Center,Academic Medical Center Amsterdam RCV000000770 SCV000992155 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 5 2018-12-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000588763 SCV000699486 pathogenic Arrhythmogenic right ventricular dysplasia/cardiomyopathy 2016-07-25 criteria provided, single submitter clinical testing Variant summary: The TMEM43 c.1073C>T (p.Ser358Leu) variant involves the alteration of a conserved nucleotide and is located in third transmembrane domain of the protein (Christensen_2011). 4/4 in silico tools predict a damaging outcome for this variant. Functional studies have shown that the S358L mutant reduces conduction velocity, increases the stiffness cell nuclei and alters the gap junction function (Siragam_PLoS One_2014 and Milting_Eur Heart J_2015). This variant was absent in 123942 control chromosomes. This variant has been widely reported as a founder mutation in Newfoundland. From a study of 15 families from Newfoundland, median age to develop an ARVD associated phenotype was 32 years for males and 44 years for females, with 100% of males and females penetrant by 63 and 76 years, respectively (Milting_Eur Heart J_2015). Haplotype analysis revealed an estimated age of 13001500 years for the mutation, which proves the European origin of the Newfoundland mutation (Milting_Eur Heart J_2015). Interestingly, this variant was also found as a confirmed de novo variant in an ARVC patient from New Zealand. Haplotype analysis revealed that the mutation occurred on a different haplotype in the patient than in the patients from Newfoundland (Baskin_HG_2013). Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Invitae RCV000000770 SCV000764088 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 5 2018-06-11 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 358 of the TMEM43 protein (p.Ser358Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be a founder variant for arrhythmogenic right ventricular cardiomyopathy (ARVC) in the region of Newfoundland (Canada), although it has been described in other populations (PMID: 18313022, 21214875, 22725725, 23810883, 24598986 ) It has also been reported to be de novo in one ARVC individual (PMID: 23812740). ClinVar contains an entry for this variant (Variation ID: 734). Experimental studies have shown that this missense change affects localization of proteins involved in conduction and alters gap junction function during transient expression assays in cardiomyocyte cultures (PMID: 25343256). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000039375 SCV000063059 pathogenic Arrhythmogenic right ventricular cardiomyopathy 2015-04-04 no assertion criteria provided clinical testing The p.Ser358Leu variant in TMEM43 has been reported in >20 families with ARVC (a t least 15 from Newfoundland), including 1 de novo occurrence and segregated wit h disease in >20 affected relatives from these families (Merner 2008, Christense n 2011, Baskin 2013, Hodgkinson 2013, Milting 2014). It was absent from large po pulation studies. In summary, this variant meets criteria to be classified as pa thogenic for autosomal dominant ARVC. ACMG/AMP Criteria applied: PS4, PP1_Strong , PM2, PM6, PP3.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000183944 SCV000740428 pathogenic not provided 2016-06-26 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000039375 SCV000987538 pathogenic Arrhythmogenic right ventricular cardiomyopathy criteria provided, single submitter clinical testing
OMIM RCV000000770 SCV000020920 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 5 2013-11-01 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000183944 SCV000280493 pathogenic not provided 2010-12-03 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. This variant was found in a large kindred in Newfoundland (Merner et al 2008) with strong segregation data supporting it's pathogenicity. In that study the variant was not observed in 208 control individuals. In silico analysis with Polyphen-2 predicts the variant to be probably damaging. The Serene at codon 358 is completely conserved across species. Merner et al reported that in their kindred of 257 affected individuals there was age-dependent but complete penetrance with a severe phenotype. The phenotype was modified by gender, with a median life expectancy of 41 years in males and 71 years in females. Heart failure was a late manifestation.

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