ClinVar Miner

Submissions for variant NM_024334.2(TMEM43):c.271A>G (p.Ile91Val) (rs144811578)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621435 SCV000735814 uncertain significance Cardiovascular phenotype 2017-04-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000777738 SCV000913698 uncertain significance Cardiomyopathy 2018-10-09 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the cytoplasmic domain of the TMEM43 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. Experimental studies have shown that this variant may cause irregular cell shape, but the clinical relevance of this observation is not clear (PMID: 21391237). This variant has been reported in an individual affected with Emery-Dreifuss muscular dystrophy-related myopathy (PMID: 21391237), as well as in a control individual (PMID: 23812740). This variant has also been identified in 18/244874 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
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).
Invitae RCV000553145 SCV000642091 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 5 2018-11-30 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.
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
OMIM RCV000033855 SCV000057760 pathogenic Emery-Dreifuss muscular dystrophy 7, autosomal dominant 2011-06-01 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.