Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000164900 | SCV000215587 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-02-15 | criteria provided, single submitter | clinical testing | The p.Q159* pathogenic mutation (also known as c.475C>T), located in coding exon 3 of the TMEM127 gene, results from a C to T substitution at nucleotide position 475. This alteration occurs at the 3' terminus of theTMEM127 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 80 amino acids of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration has been reported in a family with multiple family members diagnosed with bilateral pheochromocytomas from 48y to 72y (Qin Y et al. Nat Genet. 2010 Mar; 42(3):229-33). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Labcorp Genetics |
RCV001381352 | SCV001579708 | pathogenic | Hereditary pheochromocytoma-paraganglioma | 2020-10-06 | criteria provided, single submitter | clinical testing | This sequence change results in a premature translational stop signal in the TMEM127 gene (p.Gln159*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 80 amino acids of the TMEM127 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with paraganglioma-pheochromocytoma syndrome (PMID: 20154675). ClinVar contains an entry for this variant (Variation ID: 108). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the TMEM127 protein. Other variant(s) that disrupt this region (p.Tyr178Leufs*48) have been determined to be pathogenic (PMID: 28855235, 28384794). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. |
| Rady Children's Institute for Genomic Medicine, |
RCV000114833 | SCV005900572 | likely pathogenic | Pheochromocytoma | 2024-04-26 | criteria provided, single submitter | clinical testing | This nonsense variant is found in the last exon of TMEM127, therefore the resulting mRNA is predicted to escape nonsense-mediated decay. However, nonsense variants located downstream of this variant have been reported as disease-causing variants in the literature (PMID: 22419703, 33051659, 28567294). Loss-of-function variation in TMEM127 is an established mechanism of disease (PMID: 20301715, 16266984). This variant has been previously reported as a heterozygous change in patients with pheochromocytoma (PMID: 20154675, 33051659). The c.475C>T (p.Gln159Ter) variant is absent from the gnomAD v4 population database and thus is presumed to be rare. Based on the available evidence, c.475C>T (p.Gln159Ter) is classified as Likely Pathogenic. |
| OMIM | RCV000000128 | SCV000020271 | risk factor | Pheochromocytoma, susceptibility to | 2010-03-01 | no assertion criteria provided | literature only | |
| Familial Cancer Clinic, |
RCV000114833 | SCV000148728 | likely pathogenic - adrenal bilateral pheochromocy | Pheochromocytoma | no assertion criteria provided | not provided | Converted during submission to Likely pathogenic. |