Submissions for variant NM_017849.4(TMEM127):c.410-2A>G

dbSNP: rs121908826

Total submissions: 5

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 pheochromocytoma-paraganglioma	2020-02-27	criteria provided, single submitter	clinical testing	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. 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. 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. 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). This variant is not present in population databases (ExAC no frequency). 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.
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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000519103	SCV001931668	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000519103	SCV001951392	pathogenic	not provided		no assertion criteria provided	clinical testing