Submissions for variant NM_005534.4(IFNGR2):c.708A>T (p.Glu236Asp)

gnomAD frequency: 0.00235  dbSNP: rs121913212

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080384	SCV001031887	likely benign	Immunodeficiency 28	2024-01-08	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001080384	SCV001468489	uncertain significance	Immunodeficiency 28	2021-03-30	criteria provided, single submitter	clinical testing	IFNGR2 NM_005534.3 exon 5 p.Glu236Asp c.708A>T: This variant has not been reported in the literature but is present in 0.7% (192/24962) of African alleles including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/21-34804630-A-T?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:111250). Evolutionary conservation suggests that this variant may not impact the protein; computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387762	SCV004099840	uncertain significance	not specified	2023-09-14	criteria provided, single submitter	clinical testing	Variant summary: IFNGR2 c.708A>T (p.Glu236Asp) results in a conservative amino acid change located in a Fibronectin type III domain (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 0.00051 in 251382 control chromosomes, predominantly at a frequency of 0.0075 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance, although the high frequency in the African/African-American subpopulation and presence of a homozygote suggest the variant could be benign or display incomplete penetrance. c.708A>T has been reported in the literature in at least one homozygous individual affected with suspected Mendelian Susceptibility to Mycobacterial Disease, with a similarly affected, deceased sibling, and a demonstrated deficiency in interferon gamma production/signalling (e.g., vanColler_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26242990, 34517836). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely benign, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Human Evolutionary Genetics, Institut Pasteur	RCV000097452	SCV000121666	not provided	not provided		no assertion provided	not provided
PreventionGenetics, part of Exact Sciences	RCV003935085	SCV004748932	benign	IFNGR2-related disorder	2023-05-24	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).