ClinVar Miner

Submissions for variant NM_024334.2(TMEM43):c.947G>C (p.Trp316Ser) (rs199526104)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000776154 SCV000911157 uncertain significance Cardiomyopathy 2018-06-18 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the second transmembrane domain of the TMEM43 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in 2 individuals from one family suspected of being affected with arrhythmogenic cardiomyopathy in the literature. This variant is present in the general population and has been identified in 43/277196 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
GeneDx RCV000766918 SCV000236434 uncertain significance not provided 2019-01-21 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TMEM43 gene. The W316S variant has been reported in two individuals from one family with ARVC (Adler et al., 2016); however, specific clinical information was not provided. This variant is observed in 43/277196 (0.016%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). Nevertheless, the W316S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000457565 SCV000545860 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 5 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with serine at codon 316 of the TMEM43 protein (p.Trp316Ser). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and serine. This variant is present in population databases (rs199526104, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in two individuals in a single family affected with arrhythmogenic right ventricular dysplasia (PMID: 26743238). ClinVar contains an entry for this variant (Variation ID: 46155). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Laboratory for Molecular Medicine,Partners HealthCare 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 In summary, although data supports that the Trp316Ser variant may be pathogenic, additional studies are needed to fully assess its cl inical significance

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