ClinVar Miner

Submissions for variant NM_024334.2(TMEM43):c.166C>T (p.Arg56Cys) (rs201094625)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000767092 SCV000621042 uncertain significance not provided 2017-09-25 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TMEM43 gene. The R56C variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 7/34366 (0.02%) alleles from individuals of Latino ancestry and in 5/126586 (0.004%) alleles from individuals of European (Non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The R56C 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 analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position that is not conserved across species and where cysteine (C) is present as the wild type in at least two species.
Invitae RCV000462660 SCV000545855 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 5 2018-09-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 56 of the TMEM43 protein (p.Arg56Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs201094625, ExAC 0.03%). This variant has not been reported in the literature in individuals with TMEM43-related disease. ClinVar contains an entry for this variant (Variation ID: 406895). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000519195 SCV000731422 uncertain significance not specified 2017-01-27 criteria provided, single submitter clinical testing The p.Arg56Cys variant in TMEM43 has not been previously reported in individuals with cardiomyopathy. This variant has been identified in 3/10364 African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201094625). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg56Cys variant is uncertain.

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