ClinVar Miner

Submissions for variant NM_017849.3(TMEM127):c.532dup (p.Tyr178fs) (rs1553436874)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484919 SCV000571199 pathogenic not provided 2017-11-21 criteria provided, single submitter clinical testing This duplication of one nucleotide in TMEM127 is denoted c.532dupT at the cDNA level and p.Tyr178LeufsX48 (Y178LfsX48) at the protein level. The normal sequence, with the base that is duplicated in brackets, is CTTC[dupT]ACCT. The duplication causes a frameshift which changes a Tyrosine to a Leucine at codon 178, and creates a premature stop codon at position 48 of the new reading frame. This variant has been observed in individuals with pheochromocytomas (Bausch 2017, Deng 2017). It is predicted to cause loss of normal protein function through protein truncation, and functional work suggests unstable protein in pheochromocytoma specimens as well as activation of the mTORC1 kinase pathway, a phenomenon that has been observed in other TMEM127-associated tumors (Deng 2017). The disrupted region at the end of the gene is in the third transmembrane domain (Yao 2010). Based on the currently available information, we consider this duplication to be a pathogenic variant.
Invitae RCV001215668 SCV001387423 likely pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes 2019-07-19 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TMEM127 gene (p.Tyr178Leufs*48). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 61 amino acids of the TMEM127 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with clinical features of paraganglioma-pheochromocytoma syndrome (PMID: 28855235, 28384794). ClinVar contains an entry for this variant (Variation ID: 421874). This variant has been reported to affect TMEM127 protein 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.