Submissions for variant NM_001193304.3(TMEM127):c.117_120del (p.Ile41fs) (rs121908816)

Total submissions: 6

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	2017-07-10	criteria provided, single submitter	clinical testing	This deletion of four nucleotides in TMEM127 is denoted c.117_120delGTCT at the cDNA level and p.Ile41ArgfsX39 (I41RfsX39) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CCCT[delGTCT]ATCA. The deletion causes a frameshift which changes an Isoleucine to an Arginine at codon 41, and creates a premature stop codon at position 39 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. TMEM127 c.117_120delGTCT, also denoted c.116_119delTGTC and c.115_118delCTGT using alternate nomenclature, has been reported in individuals with early-onset and bilateral pheochromocytomas (Yao 2010, Takeichi 2012, Curr?s-Freixes 2015). We consider this variant to be pathogenic.
Invitae	RCV000556401	SCV000637904	pathogenic	Hereditary Paraganglioma-Pheochromocytoma Syndromes	2020-06-13	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. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with adrenal pheochromocytoma (PMID: 21156949, 22541004). It is also known as c.116_119delTGTC in the literature. ClinVar contains an entry for this variant (Variation ID: 126962). Loss-of-function variants in TMEM127 are known to be pathogenic (PMID: 21156949). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000574362	SCV000675298	pathogenic	Hereditary cancer-predisposing syndrome	2017-05-12	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 mutation (designated as c.116_119delTGTC) has been identified in individuals diagnosed with paragangliomas and pheochromocytomas (Takeichi N et al. Clin. Endocrinol. (Oxf), 2012 Nov;77:707-14; Yao L et al. JAMA, 2010 Dec;304:2611-9). 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.
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.