ClinVar Miner

Submissions for variant NM_024334.2(TMEM43):c.796C>T (p.Arg266Trp) (rs139842014)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000467886 SCV000545853 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 5 2019-08-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 266 of the TMEM43 protein (p.Arg266Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs139842014, ExAC 0.03%) but has not been reported in the literature in individuals with a TMEM43-related disease. ClinVar contains an entry for this variant (Variation ID: 180544). 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, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000523010 SCV000616895 uncertain significance not provided 2018-04-10 criteria provided, single submitter clinical testing The R266W variant of uncertain significance in the TMEM43 gene has not been published as pathogenic or been reported as benign to our knowledge. R266W has been observed, both independently and in conjunction with additional cardiogenetic variants, in at least three unrelated individuals referred for cardiac genetic testing at GeneDx. The R266W variant is observed in 11/34,418 (0.03%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). The R266W 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. Furthermore, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.
Color RCV000157523 SCV000913672 uncertain significance Cardiomyopathy 2020-03-04 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000157523 SCV000207268 uncertain significance Cardiomyopathy 2014-10-28 no assertion criteria provided clinical testing

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