ClinVar

Description

This sequence change creates a premature translational stop signal (p.Tyr178Leufs*48) in the TMEM127 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 61 amino acid(s) of the TMEM127 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of paraganglioma-pheochromocytoma syndrome (PMID: 28384794, 28855235; Invitae). ClinVar contains an entry for this variant (Variation ID: 421874). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects TMEM127 function (PMID: 28855235). This variant disrupts the C-terminus of the TMEM127 protein. Other variant(s) that disrupt this region (p.Ala186Argfs*44) have been observed in individuals with TMEM127-related conditions (PMID: 28384794). This suggests that this may be a clinically significant region of the protein. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.