ClinVar Miner

Submissions for variant NM_024334.3(TMEM43):c.271A>G (p.Ile91Val) (rs144811578)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766912 SCV000236442 uncertain significance not provided 2018-12-17 criteria provided, single submitter clinical testing p.Ile91Val (ATC>GTC): c.271 A>G in exon 3 of the TMEM43 gene (NM_024334.2). Although rare, mutations in the TMEM43 gene have been reported in association with ARVC (McNally E et al., 2009). A published variant of unknown significance has been identified in the TMEM43 gene. The I91V variant has been previously reported in a 63 year old female from a healthy control cohort (Kapplinger J et al., 2011). Additionally, Liang et al. (2011) identified the I91V variant in an individual with Emery-Dreifuss muscular dystrophy. The NHLBI Exome Sequencing Project reports I91V was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry. The I91V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species. Lastly, in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARRHYTHMIA panel(s).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000183950 SCV000540544 uncertain significance not specified 2016-03-31 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 paper in HGMD; ExAC: 6/8626 East Asian; ClinVar: 1 VUS
Invitae RCV000553145 SCV000642091 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 5 2019-10-30 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 91 of the TMEM43 protein (p.Ile91Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs144811578, ExAC 0.07%). This variant has been observed in an individual affected with muscular dystrophy (PMID: 21391237), but has also been observed in a healthy control individuals (PMID: 23812740, 21636032). ClinVar contains an entry for this variant (Variation ID: 40871). Experimental studies have shown that overexpressing this missense change in cell lines leads to irregular cell shape, but the clinical relevance of this observation is uncertain (PMID: 21391237). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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 RCV000621435 SCV000735814 likely benign Cardiovascular phenotype 2019-06-11 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Color RCV000777738 SCV000913698 likely benign Cardiomyopathy 2019-11-05 criteria provided, single submitter clinical testing
OMIM RCV000033855 SCV000057760 pathogenic Emery-Dreifuss muscular dystrophy 7, autosomal dominant 2011-06-01 no assertion criteria provided literature only

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