Submissions for variant NM_017849.4(TMEM127):c.280C>T (p.Arg94Trp)

gnomAD frequency: 0.00006  dbSNP: rs121908824

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229383	SCV000290377	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 94 of the TMEM127 protein (p.Arg94Trp). This variant is present in population databases (rs121908824, gnomAD 0.005%). This missense change has been observed in individual(s) with pheochromocytoma (PMID: 21156949). ClinVar contains an entry for this variant (Variation ID: 126967). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TMEM127 function (PMID: 21156949). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000567548	SCV000675308	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-26	criteria provided, single submitter	clinical testing	The p.R94W variant (also known as c.280C>T), located in coding exon 2 of the TMEM127 gene, results from a C to T substitution at nucleotide position 280. The arginine at codon 94 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been identified in individuals with paragangliomas and/or pheochromocytomas (Yao L, et al. JAMA 2010 Dec; 304(23):2611-9; Yonamine M et al. Cancers (Basel), 2021 Aug;13:). A subcellular localization assay performed by Yao, et al. demonstrated aberrant distribution of the mutant protein in the cytoplasm rather than the plasma membrane as observed in wild type protein. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Sema4, Sema4	RCV000567548	SCV002527246	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-06	criteria provided, single submitter	curation
GeneDx	RCV003236777	SCV003935576	uncertain significance	not provided	2022-12-22	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate protein mislocalization (Yao et al., 2010); This variant is associated with the following publications: (PMID: 21156949, 33051659, 34439168)
Baylor Genetics	RCV000114826	SCV005054293	uncertain significance	Pheochromocytoma	2024-03-13	criteria provided, single submitter	clinical testing
Familial Cancer Clinic, Veneto Institute of Oncology	RCV000114826	SCV000148721	likely pathogenic - adrenal pheochromocytoma	Pheochromocytoma		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.