ClinVar Miner

Submissions for variant NM_017849.4(TMEM127):c.409+1G>C

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001376818 SCV001573990 likely pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes 2020-05-12 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in the last intron (intron 3) of the TMEM127 gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individual(s) with pheochromocytoma and breast cancer (PMID: 21156949). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that disruption of this splice site disrupts mRNA splicing (PMID: 21156949). This variant disrupts transmembrane domains, TM1 and TM2, of the TMEM127 protein, which are required for subcellular localization (PMID: 21156949). While functional studies have not been performed to directly test the effect of this variant on TMEM127 protein function, this suggests that disruption of this region of the protein is causative of disease. 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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