ClinVar Miner

Submissions for variant NM_024334.2(TMEM43):c.859C>T (p.His287Tyr) (rs780299346)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183941 SCV000236433 uncertain significance not provided 2017-10-25 criteria provided, single submitter clinical testing p.His287Tyr (CAC>TAC): c.859 C>T in exon 10 of the TMEM43 gene (NM_024334.2). A variant of unknown significance has been identified in the TMEM43 gene. To our knowledge, the H287Y variant has not been published as a mutation or as a benign polymorphism. The H287Y 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. The H287Y 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. This substitution occurs at a position that is mostly conserved in mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no definitely disease-causing missense mutations in nearby residues have been reported in association with ARVC, suggesting this region of the protein may be tolerant to change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Invitae RCV000697685 SCV000826310 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 5 2018-03-16 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 287 of the TMEM43 protein (p.His287Tyr). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TMEM43-related disease. ClinVar contains an entry for this variant (Variation ID: 202121). 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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