Submissions for variant NM_017849.4(TMEM127):c.117_120del (p.Ile41fs)

dbSNP: rs121908816

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000449515	SCV000537698	pathogenic	Pheochromocytoma	2016-07-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000485576	SCV000567003	pathogenic	not provided	2024-05-09	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 37529773, 26269449, 28973655, 21156949, 37358160, 34906458, 22541004, 33051659)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000556401	SCV000637904	pathogenic	Hereditary pheochromocytoma-paraganglioma	2025-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile41Argfs*39) in the TMEM127 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMEM127 are known to be pathogenic (PMID: 20154675, 21156949). This variant is present in population databases (rs121908816, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with adrenal pheochromocytoma (PMID: 21156949, 22541004). This variant is also known as c.116_119delTGTC. ClinVar contains an entry for this variant (Variation ID: 397511). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000574362	SCV000675298	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-19	criteria provided, single submitter	clinical testing	The c.117_120delGTCT pathogenic mutation, located in coding exon 1 of the TMEM127 gene, results from a deletion of 4 nucleotides at nucleotide positions 117 to 120, causing a translational frameshift with a predicted alternate stop codon (p.I41Rfs*39). This alteration has been identified in individuals diagnosed with paragangliomas and/or pheochromocytomas (Takeichi N et al. Clin. Endocrinol. (Oxf), 2012 Nov;77:707-14; Yao L et al. JAMA, 2010 Dec;304:2611-9). Of note, this alteration is also known as c.116_119delTGTC in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Sema4, Sema4	RCV000574362	SCV002527238	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-09	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000556401	SCV002572184	pathogenic	Hereditary pheochromocytoma-paraganglioma	2022-08-19	criteria provided, single submitter	clinical testing	Variant summary: TMEM127 c.117_120delGTCT (p.Ile41ArgfsX39) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.5e-05 in 200316 control chromosomes (gnomAD). c.117_120delGTCT has been reported in the literature in multiple individuals with pheochromocytomas (e.g.Yao_2010, Takeichi_2012, Curras_Freixes_2015, Armaiz-Pena_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000449515	SCV004041267	pathogenic	Pheochromocytoma	2024-03-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000449515	SCV005663314	pathogenic	Pheochromocytoma	2024-02-14	criteria provided, single submitter	clinical testing
Familial Cancer Clinic, Veneto Institute of Oncology	RCV000449515	SCV000148714	likely pathogenic - adrenal pheochromocytoma	Pheochromocytoma		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
GenomeConnect - Invitae Patient Insights Network	RCV000449515	SCV001749822	not provided	Pheochromocytoma		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 10-11-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
PreventionGenetics, part of Exact Sciences	RCV004755920	SCV005347869	likely pathogenic	TMEM127-related disorder	2024-08-23	no assertion criteria provided	clinical testing	The TMEM127 c.117_120delGTCT variant is predicted to result in a frameshift and premature protein termination (p.Ile41Argfs*39). In the literature, this variant is also reported as c.116_119delGTCT and c.115_118delCTGT. This variant was reported in multiple individuals with pheochromocytoma (Yao et al. 2010. PubMed ID: 21156949; Lima et al. 2023. PubMed ID: 37529773; Table S1, Currás-Freixes et al. 2015. PubMed ID: 26269449). Of note, one of those individuals also had a TP53 variant and breast and pancreatic cancers (Lima et al 2023. PubMed ID: 37529773). This variant is reported in 0.0050% of alleles in individuals of African descent in gnomAD. Frameshift variants in TMEM127 are expected to be pathogenic. This variant is interpreted as likely pathogenic.