Submissions for variant NM_017849.4(TMEM127):c.2T>C (p.Met1Thr)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV004333281	SCV005027510	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-06	criteria provided, single submitter	clinical testing	The p.M1? pathogenic mutation (also known as c.2T>C) is located in coding exon 1 of the TMEM127 gene and results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). Variants affecting the initiation codon have been identified in individuals with a personal of family history of TMEM127-associated disease (Bausch B et al. JAMA Oncol. 2017 Sep;3(9):1204-1212; Eijkelenkamp K et al. Clin GEnet. 2018 May;93(5):1049-1056). Protein functional studies have shown initiation codon loss disrupts TMEM127 function (Yao L et al. JAMA. 2010 Dec;304:2611-9). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
deCODE genetics, Amgen	RCV003485907	SCV004022175	likely pathogenic	Pheochromocytoma	2023-07-21	no assertion criteria provided	research	The variant NM_017849.4:c.2T>C (chr2:96265380) in TMEM127 was detected in 4 heterozygotes out of 58K WGS Icelanders (MAF= 0,003%). This variant has not been reported in ClinVar previously. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic.