ClinVar Miner

Submissions for variant NM_024334.3(TMEM43):c.796C>T (p.Arg266Trp)

gnomAD frequency: 0.00003  dbSNP: rs139842014
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000467886 SCV000545853 uncertain significance Arrhythmogenic right ventricular dysplasia 5 2024-01-22 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 266 of the TMEM43 protein (p.Arg266Trp). This variant is present in population databases (rs139842014, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TMEM43-related conditions. ClinVar contains an entry for this variant (Variation ID: 180544). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TMEM43 protein function with a positive predictive value of 80%. 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.
GeneDx RCV000523010 SCV000616895 uncertain significance not provided 2021-09-14 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 180544; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26582918)
Color Diagnostics, LLC DBA Color Health RCV000157523 SCV000913672 uncertain significance Cardiomyopathy 2023-02-06 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 266 of the TMEM43 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Emery-Dreifuss muscular dystrophy, who also carried a pathogenic variant (c.122G>A, p.Arg41His) in the LMNA gene that could explain the observed phenotype (PMID: 29311375). This variant has been identified in 19/280930 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics RCV002408708 SCV002675760 likely benign Cardiovascular phenotype 2021-09-11 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.
Fulgent Genetics, Fulgent Genetics RCV002492613 SCV002803231 uncertain significance Arrhythmogenic right ventricular dysplasia 5; Emery-Dreifuss muscular dystrophy 7, autosomal dominant; Auditory neuropathy, autosomal dominant 3 2021-11-09 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000467886 SCV004841565 uncertain significance Arrhythmogenic right ventricular dysplasia 5 2024-07-02 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 266 of the TMEM43 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Emery-Dreifuss muscular dystrophy, who also carried a pathogenic variant (c.122G>A, p.Arg41His) in the LMNA gene that could explain the observed phenotype (PMID: 29311375). This variant has been identified in 19/280930 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Blueprint Genetics RCV000157523 SCV000207268 uncertain significance Cardiomyopathy 2014-10-28 no assertion criteria provided clinical testing

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