Submissions for variant NM_017849.4(TMEM127):c.409+7C>T

gnomAD frequency: 0.00487  dbSNP: rs189327749

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229567	SCV000290380	benign	Hereditary pheochromocytoma-paraganglioma	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000248908	SCV000313040	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000351000	SCV000432542	benign	Pheochromocytoma	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000248908	SCV000514904	likely benign	not specified	2017-06-27	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Genetic Services Laboratory, University of Chicago	RCV000248908	SCV000597497	benign	not specified	2017-08-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000248908	SCV001426816	benign	not specified	2020-07-22	criteria provided, single submitter	clinical testing	Variant summary: TMEM127 c.409+7C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0049 in 251378 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is significantly higher than the estimated maximal expected allele frequency for a pathogenic variant in TMEM127 causing Hereditary Paraganglioma-Pheochromocytoma Syndrome phenotype (3.1e-07), strongly suggesting that the variant is benign. c.409+7C>T has been reported in the literature in sequencing studies of individuals affected with Paraganglioma and/or Pheochromocytoma (example Abermil_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Paraganglioma-Pheochromocytoma Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=3)/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000248908	SCV002046811	benign	not specified	2021-04-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002256167	SCV002527254	benign	Hereditary cancer-predisposing syndrome	2020-09-15	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV001726068	SCV002544060	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	TMEM127: BP4, BS2
Ambry Genetics	RCV002256167	SCV002629308	likely benign	Hereditary cancer-predisposing syndrome	2015-02-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000351000	SCV004015618	benign	Pheochromocytoma	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001726068	SCV005259873	likely benign	not provided		criteria provided, single submitter	not provided
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000351000	SCV000734234	likely benign	Pheochromocytoma		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000248908	SCV001807703	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000248908	SCV001960067	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001726068	SCV001966538	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001726068	SCV001979899	likely benign	not provided		no assertion criteria provided	clinical testing