Submissions for variant NM_024334.3(TMEM43):c.1022G>A (p.Arg341Gln)

gnomAD frequency: 0.00002  dbSNP: rs749727938

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001190561	SCV001358070	uncertain significance	Cardiomyopathy	2022-07-12	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 341 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/250628 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001365963	SCV001562249	uncertain significance	Arrhythmogenic right ventricular dysplasia 5	2025-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 341 of the TMEM43 protein (p.Arg341Gln). This variant is present in population databases (rs749727938, gnomAD 0.01%). 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: 927343). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TMEM43 protein function with a negative 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.
Ambry Genetics	RCV002447026	SCV002679904	likely benign	Cardiovascular phenotype	2021-09-26	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.
New York Genome Center	RCV001365963	SCV004176212	uncertain significance	Arrhythmogenic right ventricular dysplasia 5	2023-07-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001365963	SCV004841596	uncertain significance	Arrhythmogenic right ventricular dysplasia 5	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 341 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/250628 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.