ClinVar Miner

Submissions for variant NM_017849.4(TMEM127):c.523G>A (p.Val175Ile)

gnomAD frequency: 0.00001  dbSNP: rs149034651
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001023785 SCV001185704 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-08 criteria provided, single submitter clinical testing The p.V175I variant (also known as c.523G>A), located in coding exon 3 of the TMEM127 gene, results from a G to A substitution at nucleotide position 523. The valine at codon 175 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was detected in a patient with pheochromocytoma and head and neck paraganglioma at age 27 (Armaiz-Pena G et al. J Clin Endocrinol Metab, 2021 01;106:e350-e364). This amino acid position is well conserved in available vertebrate species; however, isoleucine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001208850 SCV001380259 uncertain significance Hereditary pheochromocytoma-paraganglioma 2023-07-17 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 175 of the TMEM127 protein (p.Val175Ile). This variant is present in population databases (rs149034651, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of hereditary paraganglioma-pheochromocytoma syndrome (PMID: 33051659). ClinVar contains an entry for this variant (Variation ID: 825579). 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 tolerated. 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.
GeneDx RCV003229009 SCV003926297 uncertain significance not provided 2022-11-17 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21156949, 33051659)

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