Submissions for variant NM_017849.4(TMEM127):c.292G>A (p.Ala98Thr)

dbSNP: rs369144563

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000227067	SCV000290379	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 98 of the TMEM127 protein (p.Ala98Thr). This variant is present in population databases (rs369144563, gnomAD 0.009%). This missense change has been observed in individual(s) with head and neck paraganglioma (PMID: 33051659). ClinVar contains an entry for this variant (Variation ID: 241222). 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.
Ambry Genetics	RCV000562930	SCV000675313	likely benign	Hereditary cancer-predisposing syndrome	2019-04-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina	RCV001138319	SCV001298361	likely benign	Pheochromocytoma	2018-01-13	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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000227067	SCV002012382	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2021-09-09	criteria provided, single submitter	clinical testing	The TMEM127 c.292G>A (p.Ala98Thr) missense change has a maximum subpopulation frequency of 0.0088% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-96920688-C-T). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in a 44-year-old female with a head and neck paraganglioma (PMID: 33051659). The tumor sample of this individual did not demonstrate loss of heterozygosity suggesting an uncertain role this variant in tumorigenesis. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
Sema4, Sema4	RCV000562930	SCV002527248	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-30	criteria provided, single submitter	curation
GeneDx	RCV002282081	SCV002571140	uncertain significance	not provided	2024-02-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with head and neck paraganglioma (PMID: 33051659); This variant is associated with the following publications: (PMID: 21156949, 33051659)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002282081	SCV004221325	uncertain significance	not provided	2022-09-22	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000088 (10/113674 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 head and neck paraganglioma (PMID: 33051659 (2021)). 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701323	SCV005202190	likely benign	not specified	2024-07-01	criteria provided, single submitter	clinical testing	Variant summary: TMEM127 c.292G>A (p.Ala98Thr) results in a non-conservative amino acid change located in the Transmembrane protein 127, transmembrane region (IPR046795) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251384 control chromosomes (gnomAD). The observed variant frequency is approximately 216 fold of the estimated maximal expected allele frequency for a pathogenic variant in TMEM127 causing Hereditary Paraganglioma-Pheochromocytoma Syndrome phenotype (3.1e-07). c.292G>A has been reported in the literature in individuals affected with head and neck paraganglioma (Armaiz-Pena_2021). This report does not provide unequivocal conclusions about association of the variant with Hereditary Paraganglioma-Pheochromocytoma Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33051659). ClinVar contains an entry for this variant (Variation ID: 241222). Based on the evidence outlined above, the variant was classified as likely benign.