Submissions for variant NM_024334.3(TMEM43):c.659G>A (p.Arg220His)

gnomAD frequency: 0.00001  dbSNP: rs570836197

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183937	SCV000236429	uncertain significance	not provided	2020-08-11	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32880476)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000642421	SCV000764099	uncertain significance	Arrhythmogenic right ventricular dysplasia 5	2024-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 220 of the TMEM43 protein (p.Arg220His). This variant is present in population databases (rs570836197, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of TMEM43-related conditions (PMID: 32880476). ClinVar contains an entry for this variant (Variation ID: 202117). 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.
Color Diagnostics, LLC DBA Color Health	RCV001182741	SCV001348299	uncertain significance	Cardiomyopathy	2023-03-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 220 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 10/282658 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	RCV002362945	SCV002663412	likely benign	Cardiovascular phenotype	2024-10-30	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.
All of Us Research Program, National Institutes of Health	RCV000642421	SCV004841542	uncertain significance	Arrhythmogenic right ventricular dysplasia 5	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 220 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 10/282658 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.
PreventionGenetics, part of Exact Sciences	RCV003947549	SCV004765063	uncertain significance	TMEM43-related disorder	2023-11-16	no assertion criteria provided	clinical testing	The TMEM43 c.659G>A variant is predicted to result in the amino acid substitution p.Arg220His. This variant was reported as uncertain significance in an individual with dilated cardiomyopathy (Table S4, Verdonschot et al. 2020. PubMed ID: 32880476). This variant is reported in 0.0065% of alleles in individuals of South Asian in gnomAD (http://gnomad.broadinstitute.org/variant/3-14176345-G-A?dataset=gnomad_r2_1). At this time, the clinical significance of this variant is uncertain.