ClinVar Miner

Submissions for variant NM_017849.3(TMEM127):c.570del (p.Thr191fs) (rs1215337884)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000572543 SCV000675332 likely pathogenic Hereditary cancer-predisposing syndrome 2016-12-27 criteria provided, single submitter clinical testing The c.570delC variant, located in coding exon 3 of the TMEM127 gene, results from a deletion of one nucleotide at nucleotide position 570, causing a translational frameshift with a predicted alternate stop codon (p.T191Rfs*116). This frameshift occurs at the 3' terminus of TMEM127, is not expected to trigger nonsense-mediated mRNA decay, impacts the last 54 amino acids, and results in the elongation of the protein by 65 amino acids. The exact functional impact of these inserted amino acids is unknown at this time. An alteration resulting in the same elongation (c.572delC; p.T191RFS*116) has been previously identified in an individual with bilateral pheochromocytoma (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.
Invitae RCV001056017 SCV001220436 likely pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes 2019-02-27 criteria provided, single submitter clinical testing This sequence change results in a frameshift in the TMEM127 gene (p.Thr191Argfs*116). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 48 amino acids of the TMEM127 protein and extend the protein by an additional 67 amino acids. This variant is not present in population databases (ExAC no frequency). The p.Thr191Argfs*116 variant has been observed in individuals with pheochromocytoma (PMID: 26960314,28567294, Invitae). ClinVar contains an entry for this variant (Variation ID: 486549). This variant disrupts the C-terminus of the TMEM127 protein. Other variant(s) that disrupt this region (p.Met214Serfs98*) have been observed in individuals with TMEM127-related conditions (PMID: 21156949). 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.

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