Submissions for variant NM_024334.3(TMEM43):c.83G>A (p.Arg28Gln)

gnomAD frequency: 0.00003  dbSNP: rs757651177

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000550780	SCV000642108	uncertain significance	Arrhythmogenic right ventricular dysplasia 5	2025-01-12	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 28 of the TMEM43 protein (p.Arg28Gln). This variant is present in population databases (rs757651177, gnomAD 0.008%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25351510). ClinVar contains an entry for this variant (Variation ID: 466424). 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	RCV001189670	SCV001357006	uncertain significance	Cardiomyopathy	2023-02-22	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 28 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 been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 25351510). This variant has been identified in 6/282762 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778997	SCV002014824	uncertain significance	not specified	2021-10-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002438388	SCV002679806	uncertain significance	Cardiovascular phenotype	2024-06-28	criteria provided, single submitter	clinical testing	The c.83G>A (p.R28Q) alteration is located in exon 2 (coding exon 2) of the TMEM43 gene. This alteration results from a G to A substitution at nucleotide position 83, causing the arginine (R) at amino acid position 28 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002483425	SCV002782838	uncertain significance	Arrhythmogenic right ventricular dysplasia 5; Emery-Dreifuss muscular dystrophy 7, autosomal dominant; Auditory neuropathy, autosomal dominant 3	2021-10-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000550780	SCV004841461	uncertain significance	Arrhythmogenic right ventricular dysplasia 5	2024-09-28	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 28 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 been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 25351510). This variant has been identified in 6/282762 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786222	SCV000924960	uncertain significance	not provided	2017-06-12	no assertion criteria provided	provider interpretation	Found at our center in an infant being evaluated for LQTS, which is not a condition associated with the TMEM43 gene. He had an Arrhythmia Comprehensive Panel with the Invitae laboratory. One variant was reported: TMEM43, Exon 2, c.83G>A (p.Arg28Gln; R28Q), heterozygous (NM_024334.2) Chromosome position: 3:14170982 G / A Based on the information reviewed below, we classify this as a VUS, probably benign, concluding that it should not be used for diagnosis or for predictive testing. This variant has not previously been reported in the literature in association with disease. Another variant at this same codon, p.Arg28Trp, however, is currently listed in ClinVar as Benign by LMM, Invitae, Ambry, and GeneDx laboratories, which suggests that this codon may be tolerant of change. This is a nonconservative sequence change that replaces a positively-charged arginine with a polar glutamine at codon 28. The arginine residue is highly conserved across vertebrates, although it is a Lysine in at least one species of fish. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. This variant is present in 6 out of ~140,000 individuals in the gnomAD database. Specifically, it is present in 2 African, 1 South Asian, 1 Latino, and 2 non-Finnish European individuals in gnomAD. Overall MAF in the population is 0.002%. Highest ethnicity-specific MAF is 0.008% in individuals with African ancestry. Of note, another variant at this same codon, p.Arg28Trp, is considered benign by multiple clinical labs and has an overall MAF of 0.3%, with a MAF of over 1% in some ethnicities.
PreventionGenetics, part of Exact Sciences	RCV003962528	SCV004781404	uncertain significance	TMEM43-related disorder	2024-02-09	no assertion criteria provided	clinical testing	The TMEM43 c.83G>A variant is predicted to result in the amino acid substitution p.Arg28Gln. This variant was reported in a hypertrophic cardiomyopathy cohort; however, no additional studies were performed to help assess the pathogenicity of this variant (Table S1, Lopes et al. 2014. PubMed ID: 25351510). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.