Submissions for variant NM_024334.3(TMEM43):c.947G>C (p.Trp316Ser)

gnomAD frequency: 0.00004  dbSNP: rs199526104

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039395	SCV000063079	uncertain significance	not specified	2012-03-22	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The Trp316Ser v ariant (TMEM3) has not been reported in the literature but has been identified i n one individual with clinical features of ARVD/C by our laboratory. Computatio nal analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPh en2, and SIFT) suggest that the Trp316Ser variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In additi on, this variant has been identified in 0.01% (1/7020) of European American chro mosomes from a broad population by the NHLBI Exome Sequencing Project (http://ev s.gs.washington.edu/EVS/). In summary, although data supports that the Trp316Ser variant may be pathogenic, additional studies are needed to fully assess its cl inical significance
GeneDx	RCV000766918	SCV000236434	uncertain significance	not provided	2025-02-18	criteria provided, single submitter	clinical testing	Reported in two individuals from one family with ARVC (PMID: 26743238) and in individuals with cardiomyopathy in published literature (PMID: 30847666, 32880476); some individuals harbored additional cardiogenetic variants; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32880476, 30847666, 28301460, 26743238)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457565	SCV000545860	uncertain significance	Arrhythmogenic right ventricular dysplasia 5	2025-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 316 of the TMEM43 protein (p.Trp316Ser). This variant is present in population databases (rs199526104, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of TMEM43-related conditions (PMID: 26743238, 32880476). ClinVar contains an entry for this variant (Variation ID: 46155). 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	RCV000776154	SCV000911157	uncertain significance	Cardiomyopathy	2023-02-22	criteria provided, single submitter	clinical testing	This missense variant replaces tryptophan with serine at codon 316 of the TMEM43 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 2 related individuals suspected of having arrhythmogenic cardiomyopathy (PMID: 26743238), and in an individual affected with dilated cardiomyopathy (PMID: 32880476). This variant has also been identified in 44/282844 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population suggests this variant may not be disease-causing, additional studies are necessary 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	RCV000039395	SCV001426827	uncertain significance	not specified	2020-07-27	criteria provided, single submitter	clinical testing	Variant summary: TMEM43 c.947G>C (p.Trp316Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 251442 control chromosomes (gnomAD). The observed variant frequency is approximately 20-fold of the estimated maximal expected allele frequency for a pathogenic variant in TMEM43 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (8.3e-06), strongly suggesting that the variant is benign. W316S has been reported in the literature in 2 individuals from one family affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (Adler_2016). In addition, one ClinVar submitter reports internal data of the variant identified in one individual with clinical features of ARVD/C (SCV000063079.6). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. A co-occurrence with a pathogenic variant has been reported (LMNA c.949G>A , p.Glu317Lys; Internal testing). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002496628	SCV002814328	uncertain significance	Arrhythmogenic right ventricular dysplasia 5; Emery-Dreifuss muscular dystrophy 7, autosomal dominant; Auditory neuropathy, autosomal dominant 3	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000766918	SCV003825409	likely benign	not provided	2023-09-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003372610	SCV004065400	benign	Cardiovascular phenotype	2023-06-27	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
CeGaT Center for Human Genetics Tuebingen	RCV000766918	SCV004149226	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	TMEM43: BS1
All of Us Research Program, National Institutes of Health	RCV000457565	SCV004841583	uncertain significance	Arrhythmogenic right ventricular dysplasia 5	2024-09-03	criteria provided, single submitter	clinical testing	This missense variant replaces tryptophan with serine at codon 316 of the TMEM43 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 2 related individuals suspected of having arrhythmogenic cardiomyopathy (PMID: 26743238), and in an individual affected with dilated cardiomyopathy (PMID: 32880476). This variant has also been identified in 44/282844 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population suggests this variant may not be disease-causing, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Clinical Genomics Laboratory, Stanford Medicine	RCV000457565	SCV005903445	uncertain significance	Arrhythmogenic right ventricular dysplasia 5	2023-06-07	criteria provided, single submitter	clinical testing	The p.Trp316Ser variant in the TMEM43 gene has been previously reported in 1 individual with dilated cardiomyopathy and 1 individual with arrhythmogenic right ventricular dysplasia/cardiomyopathy and cosegregated with disease in 1 affected relative (Adler et al., 2016; Verdonschot et al., 2020). This variant has also been identified in 11/30616 South Asian chromosomes (44/282844) chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is present in ClinVar (Variation ID: 46155). Computational tools predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Trp316Ser variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: BS1; PP3]
Clinical Genetics, Academic Medical Center	RCV000766918	SCV001922499	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000766918	SCV001955982	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004748545	SCV005355485	uncertain significance	TMEM43-related disorder	2024-07-08	no assertion criteria provided	clinical testing	The TMEM43 c.947G>C variant is predicted to result in the amino acid substitution p.Trp316Ser. This variant was reported in an individual with dilated cardiomyopathy ( Supplemental table 4 Verdonschot et al 2020. PubMed ID: 32880476). This variant is reported in 0.036% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.