ClinVar Miner

Submissions for variant NM_024334.3(TMEM43):c.718C>T (p.Arg240Cys) (rs367910936)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766915 SCV000236431 uncertain significance not provided 2018-10-29 criteria provided, single submitter clinical testing The R240C variant of uncertain significance in the TMEM43 gene has been reported in one individual with ARVD/C; however, this individual also harbors a deletion of exons 1-4 in the PKP2 gene (Kapplinger et al., 2011). This variant has also been identified independently and/or in conjunction with additional cardiogenetic variants in individuals referred for genetic testing at GeneDx. So far, segregation data is limited or absent for these individuals. This variant is observed in 46/275704 (0.02%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). Nevertheless, the R240C 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. 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000183939 SCV000540545 uncertain significance not specified 2016-03-31 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 paper in HGMD; ExAC: 2/6110 Finnish chromosomes; ClinVar: 1 VUS
Ambry Genetics RCV000618132 SCV000736047 uncertain significance Cardiovascular phenotype 2019-10-17 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000642423 SCV000764101 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 5 2019-10-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 240 of the TMEM43 protein (p.Arg240Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs367910936, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individuals with arrhythmogenic right ventricular dysplasia/cardiomyopathy (PMID: 21636032, 25820315). However, in one of these individuals, a pathogenic allele was also identified in PKP2, which suggests that this c.718C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 202119). 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"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769156 SCV000900530 uncertain significance Cardiomyopathy 2017-05-16 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000766915 SCV001153807 uncertain significance not provided 2018-06-01 criteria provided, single submitter clinical testing
Color RCV000769156 SCV001352902 uncertain significance Cardiomyopathy 2019-12-30 criteria provided, single submitter clinical testing

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