ClinVar Miner

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

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Total submissions: 3
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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 2020-02-27 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.
Ambry Genetics RCV001021873 SCV001183542 likely pathogenic Hereditary cancer-predisposing syndrome 2018-12-12 criteria provided, single submitter clinical testing The c.410-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 3 in the TMEM127 gene. This mutation has been reported in a homozygous state in an individual diagnosed with bilateral pheochromocytoma at age 31 as well as dysmorphic features and intellectual disability (Eijkelenkamp K et al. Clin. Genet., 2018 May;93:1049-1056). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. 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.

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