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

gnomAD frequency: 0.00009  dbSNP: rs144811578

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766912	SCV000236442	uncertain significance	not provided	2022-04-28	criteria provided, single submitter	clinical testing	Reported in an individual with LGMD (Liang et al., 2001) and in three individuals with diffuse myofilament lysis, two of whom harbored additional disease-related variants (Saito et al., 2021); Reported in an individual from a control cohort (Kapplinger et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; Transfected HeLa cells with overexpression of the p.(I91V) variant showed an abnormal nuclear shape (Liang et al., 2011), although the clinical relevance of this finding is not well established; This variant is associated with the following publications: (PMID: 24598986, 23812740, 21391237, 21636032, 34486814)
Laboratory for Molecular Medicine, Mass General Brigham 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 dysplasia 5	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 91 of the TMEM43 protein (p.Ile91Val). This variant is present in population databases (rs144811578, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with muscular dystrophy (PMID: 21391237, 21636032, 23812740). ClinVar contains an entry for this variant (Variation ID: 40871). 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, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TMEM43 function (PMID: 21391237). 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	This alteration is classified as likely benign based on a combination of the following: 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.
Color Diagnostics, LLC DBA Color Health	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