ClinVar Miner

Submissions for variant NM_017849.3(TMEM127):c.245-1G>C (rs121908821)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000692290 SCV000820104 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes 2020-09-02 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 2 of the TMEM127 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in an individual affected with bilateral pheochromocytoma (PMID: 20154675). ClinVar contains an entry for this variant (Variation ID: 571215). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TMEM127 are known to be pathogenic (PMID: 20154675, 21156949). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001015587 SCV001176436 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-10 criteria provided, single submitter clinical testing The c.245-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 2 of the TMEM127 gene. This nucleotide position is highly conserved in available vertebrate species. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
New York Genome Center RCV001420569 SCV001622881 likely pathogenic Pheochromocytoma 2020-06-19 criteria provided, single submitter clinical testing
New York Genome Center RCV001420570 SCV001622882 uncertain significance See cases 2020-06-19 criteria provided, single submitter clinical testing

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