Submissions for variant NM_017849.4(TMEM127):c.121A>G (p.Ile41Val)

gnomAD frequency: 0.00006  dbSNP: rs760633411

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000574095	SCV000664467	likely benign	Hereditary cancer-predisposing syndrome	2021-02-19	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000639355	SCV000760927	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 41 of the TMEM127 protein (p.Ile41Val). This variant is present in population databases (rs760633411, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TMEM127-related conditions. ClinVar contains an entry for this variant (Variation ID: 480774). 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. 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000760995	SCV000890910	uncertain significance	Acute myeloid leukemia	2016-12-22	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002289801	SCV002580278	uncertain significance	Pheochromocytoma	2021-09-06	criteria provided, single submitter	clinical testing
GeneDx	RCV003153735	SCV003842832	uncertain significance	not provided	2022-09-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 20923864)
Baylor Genetics	RCV002289801	SCV004206180	uncertain significance	Pheochromocytoma	2024-03-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003900253	SCV004709962	uncertain significance	TMEM127-related disorder	2024-02-21	no assertion criteria provided	clinical testing	The TMEM127 c.121A>G variant is predicted to result in the amino acid substitution p.Ile41Val. This variant has been reported in an healthy control from a cancer study (Burnichon et al. 2011. PubMed ID: 20923864, referred to as c.121A>G; p.Ile41Val). This variant is reported in 0.018% of alleles in individuals of South Asian descent in gnomAD and has conflicting interpretations in ClinVar ranging from uncertain to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/480774). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.