ClinVar Miner

Submissions for variant NM_024334.2(TMEM43):c.520G>A (p.Ala174Thr) (rs397517385)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766914 SCV000236455 uncertain significance not provided 2014-09-09 criteria provided, single submitter clinical testing p.Ala174Thr (GCA>ACA): c.520 G>A in exon 7 of the TMEM43 gene (NM_024334.2). Although rare, mutations in the TMEM43 gene have been reported in association with ARVC (McNally E et al., 2009). A variant of unknown significance has been identified in the TMEM43 gene. The A174T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The A174T 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 A174T 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. Additionally, this substitution occurs at a position that is conserved among 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, missense mutations in nearby residues have not been reported, indicating this region of the protein may be tolerant of 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).
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000039388 SCV000063072 uncertain significance not specified 2012-05-01 criteria provided, single submitter clinical testing The Ala174Thr variant (TMEM43) has not been reported in the literature nor previ ously identified by our laboratory. It was absent from >3,000 European American individuals sequenced by the NHLBI exome sequencing project (http://evs.gs.washi ngton.edu/EVS). This low frequency is consistent with a disease causing role but insufficient to establish this with confidence. The amino acid alanine (Ala) at this position is highly conserved in evolutionarily distant species but additio nal computational analyses (biochemical amino acid properties, AlignGVGD, PolyPh en2, and SIFT) do not provide strong support for or against an impact to the pro tein of this change. In summary, additional information is needed to fully asses s the clinical significance of the Ala174Thr variant.

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