ClinVar Miner

Submissions for variant NM_024334.2(TMEM43):c.337G>A (p.Val113Met) (rs572474708)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766913 SCV000236445 uncertain significance not provided 2017-07-17 criteria provided, single submitter clinical testing p.Val113Met (GTG>ATG): c.337 G>A in exon 4 of the TMEM43 gene (NM_024334.2). The Val113Met variant in the TMEM43 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Val113Met results in a conservative amino acid substitution of one non-polar amino acid residue for another at a position that is well conserved across species. In silico analysis predicts Val113Met is probably damaging to the protein structure/function. The Val113Met 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, indicating this region of the protein may be tolerant of change.With the clinical and molecular information available at this time, we cannot definitively determine if Val113Met is a disease-causing mutation or a rare benign variant. The variant is found in ARRHYTHMIA panel(s).
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000183952 SCV000280494 uncertain significance not specified 2013-11-25 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Val113Met (V113M; c.337 G>A) in the TMEM43 gene. Of note, Kapplinger et al. (2011) presented evidence for a significant yield of rare missense variants in the ARVC genes of presumably healthy controls from various ethnicities. According to their data, 16% of 427 controls hosted missense variants—similar to the 21% yield in 175 Dutch and U.S. ARVC cases. This is a reminder that missense variants of unknown significance in ARVC patients need to be interpreted with caution. This variant has not been previously reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Variation at nearby residues has not been reported in HGMD in association with ARVC. This is a conservative amino acid change, resulting in the replacement of a valine (nonpolar) with a methionine (nonpolar). Valine at this location is 100% conserved across 9 mammalian species. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging” with a score of 0.986. In total the variant has not been seen in ~6500 individuals from publicly available population datasets. There is no variation at this residue in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. There is also no variation at this codon listed in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP) or 1000 genomes (http://browser.1000genomes.org)

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