ClinVar Miner

Submissions for variant NM_024334.2(TMEM43):c.323T>C (p.Val108Ala) (rs182351748)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172119 SCV000051058 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000172119 SCV000236444 uncertain significance not provided 2017-12-04 criteria provided, single submitter clinical testing p.Val108Ala (GTC>GCC): c.323 T>C in exon 4 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 V108A variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The V108A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is class conserved across species. Nevertheless, the V108A 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. Another missense mutation in a nearby residue (P111L) has been reported in association with ARVC, supporting the functional importance of this region of the protein. 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 ARVC, CARDIOMYOPATHY panel(s).
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000152048 SCV000200641 uncertain significance not specified 2015-03-12 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Val108Ala var iant in TMEM43 has been identified in 1 Asian individual with HCM, who carried a pathogenic variant in a different HCM gene (LMM unpublished data). It has also been identified in 0.2% (19/8584) of East Asian chromosomes by the Exome Aggreg ation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs182351748). Comp utational prediction tools and conservation analysis do not provide strong suppo rt for or against an impact to the protein. In summary, while the clinical signi ficance of the p.Val108Ala variant is uncertain, its frequency suggests that it is more likely to be benign.

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