Submissions for variant NM_024334.2(TMEM43):c.244C>G (p.Pro82Ala) (rs148171303)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183949	SCV000236441	uncertain significance	not provided	2014-06-06	criteria provided, single submitter	clinical testing	p.Pro82Ala (CCG>GCG): c.244 C>G in exon 3 of the TMEM43 gene (NM_024334.2). A variant of unknown significance has been identified in the TMEM43 gene. The P82A variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The P82A 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 not well conserved across species. Consequently, in silico analysis predicts this variant likely does not alter the protein structure/function. No missense mutations in nearby residues have been reported in association with ARVC, suggesting this region of the protein may be tolerant of change. Nevertheless, the P82A variant was not observed with any significant frequency 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. 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 ARRHYTHMIA panel(s).
Invitae	RCV000824019	SCV000964894	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy, type 5	2018-09-05	criteria provided, single submitter	clinical testing	This sequence change replaces proline with alanine at codon 82 of the TMEM43 protein (p.Pro82Ala). The proline residue is moderately conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs148171303, 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: 202126). 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.