ClinVar Miner

Submissions for variant NM_017849.3(TMEM127):c.464T>A (p.Leu155Ter) (rs886039439)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000256121 SCV000321965 likely pathogenic not provided 2016-01-29 criteria provided, single submitter clinical testing This variant is denoted TMEM127 c.464T>A at the cDNA level and p.Leu155Ter (L155X) at the protein level. The substitution creates a nonsense variant, which changes a Leucine to a premature stop codon (TTG>TAG) , and is predicted to cause loss of normal protein function through protein truncation. Although this variant has not, to our knowledge, been reported in the literature, it is considered likely pathogenic.
Invitae RCV000558429 SCV000637924 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes 2020-09-23 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the TMEM127 mRNA at codon 157 (p.Gln157*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 84 amino acids of the TMEM127 protein including the transmembrane domain 3 (TM3) (PMID: 21156949). This variant is not present in population databases (ExAC no frequency). This particular variant has been reported individuals affected with pheochromocytoma and paraganglioma (PMID: 26960314, Invitae). ClinVar contains an entry for this variant (Variation ID: 265271). A different truncation downstream of this variant (p.Gln157*) has been reported in individuals affected with pheochromocytoma and determined to be pathogenic (PMID: 22419703, Invitae). This suggests that deletion of this region of the TMEM127 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000564643 SCV000675310 likely pathogenic Hereditary cancer-predisposing syndrome 2019-01-11 criteria provided, single submitter clinical testing The p.L155* variant (also known as c.464T>A), located in coding exon 3 of the TMEM127 gene, results from a T to A substitution at nucleotide position 464. This changes the amino acid from a leucine to a stop codon within coding exon 3. This alteration has been reported as a disease-causing mutation in a 51 year old patient with bilateral pheochromocytoma and intra-abdominal and head/neck paraganglioma (Patócs A et al. Pathol. Oncol. Res., 2016 Oct;22:673-9). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Division of Medical Genetics, University of Washington RCV001250425 SCV001424779 pathogenic Pheochromocytoma 2019-02-12 criteria provided, single submitter clinical testing The c.464T>A variant causes the introduction of a premature termination codon which leads to a truncated protein. The c.464T>A variant has been reported in the literature in individuals with paraganglioma and pheochromocytoma [Patocs 2016]. This variant has an overall allele frequency of 0.00001 in the Genome Aggregation Database (gnomad.broadinstitute.org). Thus, this variant is considered pathogenic.

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