ClinVar Miner

Submissions for variant NM_017849.3(TMEM127):c.281G>A (p.Arg94Gln) (rs746831347)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000308137 SCV000432547 likely benign Pheochromocytoma 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae RCV000639359 SCV000760931 uncertain significance Hereditary Paraganglioma-Pheochromocytoma Syndromes 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 94 of the TMEM127 protein (p.Arg94Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs746831347, ExAC 0.003%). This variant has been observed in individual(s) with abdominal paraganglioma (PMID: 31666924). ClinVar contains an entry for this variant (Variation ID: 337506). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C3). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Fulgent Genetics,Fulgent Genetics RCV000308137 SCV000895511 uncertain significance Pheochromocytoma 2018-10-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV001016682 SCV001177663 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-05 criteria provided, single submitter clinical testing The p.R94Q variant (also known as c.281G>A), located in coding exon 2 of the TMEM127 gene, results from a G to A substitution at nucleotide position 281. The arginine at codon 94 is replaced by glutamine, an amino acid with highly similar properties. A different alteration at this position, p.R94W, has been identified in an individual with sporadic nonmalignant pheochromocytoma; cellular localization studies demonstrated that this protein has aberrant distribution in the cytoplasm (Yao L et al. JAMA 2010 Dec; 304(23):2611-9). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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