ClinVar Miner

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

gnomAD frequency: 0.00003  dbSNP: rs776581325
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Total submissions: 2
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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.

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