Submissions for variant NM_005534.4(IFNGR2):c.436A>G (p.Ile146Val)

gnomAD frequency: 0.00003  dbSNP: rs776581325

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193482	SCV001362355	uncertain significance	not specified	2019-01-18	criteria provided, single submitter	clinical testing	Variant summary: IFNGR2 c.436A>G (p.Ile146Val) results in a conservative amino acid change located in the Fibronectin type III domain & Interferon/interleukin receptor domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.3e-05 in 246128 control chromosomes, predominantly at a frequency of 0.00054 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in IFNGR2 causing Interferon Gamma Receptor Deficiency (7.3e-05 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.436A>G in individuals affected with Interferon Gamma Receptor Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001876251	SCV002123676	uncertain significance	Immunodeficiency 28	2022-07-13	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 146 of the IFNGR2 protein (p.Ile146Val). This variant is present in population databases (rs776581325, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with IFNGR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 928893). 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 valine 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.