ClinVar Miner

Submissions for variant NM_017849.3(TMEM127):c.410-2A>G (rs121908826)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519103 SCV000618440 pathogenic not provided 2017-05-01 criteria provided, single submitter clinical testing This variant is denoted TMEM127 c.410-2A>G or IVS3-2A>G and consists of an A>G nucleotidesubstitution at the -2 position of intron 3 of the TMEM127 gene. This variant destroys a canonical splice acceptor siteand is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published inthe literature. Based on the current evidence, we consider this variant to be pathogenic.
Invitae RCV000699788 SCV000828515 likely pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes 2018-12-27 criteria provided, single submitter clinical testing This sequence change affects an acceptor 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). This variant has been observed as homozygous in an individual affected with bilateral pheochromocytoma (PMID: 29282712). ClinVar contains an entry for this variant (Variation ID: 449954). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. A different variant affecting this nucleotide (c.410-2A>C, also known as IVS3-2A>C) has been determined to be pathogenic (PMID: 25389632, 20154675, 21156949). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.