Submissions for variant NM_024334.3(TMEM43):c.424G>A (p.Glu142Lys)

gnomAD frequency: 0.00069  dbSNP: rs145619906

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172593	SCV000051424	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039386	SCV000063070	uncertain significance	not specified	2015-04-10	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Glu142Lys var iant in TMEM43 has been previously reported in 3 individuals with ARVC/D (Baskin 2013, Haywood 2013) and was identified by our laboratory in 1 Caucasian child w ith congenital DCM. In addition, this variant has been identified in 0.1% (49/66 614) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs145619906) and was also identified in 1 homozygo us reportedly healthy control individual (Haywood 2013). Computational predictio n tools and conservation analysis suggest that this variant may impact the prote in, though this information is not predictive enough to determine pathogenicity. In summary, while the clinical significance of the p.Glu142Lys variant is uncer tain, the frequency of this variant and its presence in an unaffected homozygous control individual suggests that it is more likely to be benign.
GeneDx	RCV000172593	SCV000236427	likely benign	not provided	2021-07-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27153395, 23812740, 23161701, 24598986, 23861362, 30276209, 30847666, 31402444)
Ambry Genetics	RCV000250239	SCV000318759	likely benign	Cardiovascular phenotype	2023-05-25	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084741	SCV000545857	likely benign	Arrhythmogenic right ventricular dysplasia 5	2024-01-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001188634	SCV001355720	likely benign	Cardiomyopathy	2019-11-05	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000172593	SCV003825410	uncertain significance	not provided	2023-09-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039386	SCV004222705	likely benign	not specified	2023-11-15	criteria provided, single submitter	clinical testing	Variant summary: TMEM43 c.424G>A (p.Glu142Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00055 in 251372 control chromosomes, predominantly at a frequency of 0.00099 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 119-fold of the estimated maximal expected allele frequency for a pathogenic variant in TMEM43 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (8.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.424G>A has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, without strong evidence for causality (e.g. Haywood_2013, Baskin_2013, Donate Puertas_2018, Begay_2016, van Lint_2019) and has also been reported in the homozygous state in an unaffected control individual (Haywood_2013). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23812740, 28008423, 30276209, 23161701, 30847666). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Four submitters classified the variant as likely benign and two classified it as VUS. Based on the evidence outlined above, the variant was classified as likely benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000172593	SCV001741915	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000172593	SCV001917858	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000172593	SCV001932920	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000172593	SCV001954971	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172593	SCV001973322	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003934940	SCV004756693	likely benign	TMEM43-related disorder	2023-01-27	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).