Submissions for variant NM_017849.4(TMEM127):c.217G>C (p.Gly73Arg)

gnomAD frequency: 0.00004  dbSNP: rs121908820

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000542037	SCV000637914	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2023-09-09	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this missense change does not substantially affect TMEM127 function (PMID: 32575117). 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. ClinVar contains an entry for this variant (Variation ID: 126965). This missense change has been observed in individual(s) with pheochromocytoma (PMID: 21156949). This variant is present in population databases (rs121908820, gnomAD 0.008%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 73 of the TMEM127 protein (p.Gly73Arg).
Ambry Genetics	RCV001014707	SCV001175451	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-23	criteria provided, single submitter	clinical testing	The p.G73R variant (also known as c.217G>C), located in coding exon 1 of the TMEM127 gene, results from a G to C substitution at nucleotide position 217. The glycine at codon 73 is replaced by arginine, an amino acid with dissimilar properties. This variant has been detected in an Italian male with an apparently sporadic adrenal paraganglioma diagnosed at age 44 (Yao L et al, JAMA 2010 Dec; 304(23):2611-9). 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.
Baylor Genetics	RCV000114823	SCV004206173	uncertain significance	Pheochromocytoma	2023-07-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477492	SCV004221321	uncertain significance	not provided	2023-05-10	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000081 (10/123534 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with pheochromocytoma (PMID: 21156949 (2010)). A published functional study has reported that this variant does not have a deleterious effect on TMEM127 protein localization and expression (PMID: 32575117 (2020)), however additional studies are required to determine the global effect of this variant on TMEM127 protein function. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Familial Cancer Clinic, Veneto Institute of Oncology	RCV000114823	SCV000148718	likely pathogenic - adrenal pheochromocytoma	Pheochromocytoma		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
CSER _CC_NCGL, University of Washington	RCV000114823	SCV000190640	likely benign	Pheochromocytoma	2014-06-01	no assertion criteria provided	research