Submissions for variant NM_002185.5(IL7R):c.536C>T (p.Thr179Met)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003074928	SCV003460756	uncertain significance	Immunodeficiency 104	2022-06-18	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 179 of the IL7R protein (p.Thr179Met). This variant is present in population databases (rs200751605, gnomAD 0.1%). This missense change has been observed in individual(s) with severe combined immunodeficiency due to IL7R-alpha deficiency (PMID: 30290665). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003324070	SCV004029414	uncertain significance	not specified	2023-07-27	criteria provided, single submitter	clinical testing	Variant summary: IL7R c.536C>T (p.Thr179Met) results in a non-conservative amino acid change located in the Fibronectin type III (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 250742 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in IL7R causing Severe Combined Immunodeficiency (0.00012 vs 0.0011), allowing no conclusion about variant significance. c.536C>T has been reported in the literature as a bi-allelic compound heterozygous genotype with another variant of uncertain clinical significance in an individual affected with a clinical diagnosis of T-negative/B-plus IL7R-alpha Severe Combined Immunodeficiency (example, Chi-2018). These report(s) do not provide unequivocal conclusions about association of the variant with Severe Combined Immunodeficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30290665). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.