ClinVar Miner

Submissions for variant NM_024334.2(TMEM43):c.659G>A (p.Arg220His) (rs570836197)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183937 SCV000236429 uncertain significance not provided 2014-02-19 criteria provided, single submitter clinical testing p.Arg220His (CGC>CAC): c.659 G>A in exon 8 of the TMEM43 gene (NM_024334.2). The R220H variant in the TMEM43 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The R220H variant is a conservative amino acid substitution as these residues share similar properties, and are least likely to impact secondary structure. The R220 residue is mostly conserved in mammals. In silico analysis predicts R220H is possibly damaging to the protein structure/function. The R220H variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, no mutations in nearby residues have been reported in association with ARVC, suggesting this region of the protein may be tolerant to change. With the clinical and molecular information available at this time, we cannot definitively determine if R220H is a disease-causing mutation or a rare benign variant. The variant is found in ARRHYTHMIA panel(s).
Invitae RCV000642421 SCV000764099 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 5 2017-11-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 220 of the TMEM43 protein (p.Arg220His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs570836197, ExAC 0.01%). This variant has not been reported in the literature in individuals with TMEM43-related disease. ClinVar contains an entry for this variant (Variation ID: 202117). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.

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