Submissions for variant NM_002185.5(IL7R):c.617G>A (p.Arg206Gln)

gnomAD frequency: 0.00005  dbSNP: rs193922644

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	RCV000030064	SCV000052719	uncertain significance	not specified	2019-01-16	criteria provided, single submitter	clinical testing	Variant summary: IL7R c.617G>A (p.Arg206Gln) results in a conservative amino acid change located in the Fibronectin type III domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 276662 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. This variant was initially identified in a 11 year old male undergoing SCID evaluation at our laboratory in compound heterozygosity with another pathogenic variant, c.616C>T (p.Arg206*). The phase of both variants was confirmed by family testing. No other pathogenic/likely pathogenic variants were identified in the IL7R, CD3D, CD3E genes analyzed. This patient is lost to additional follow-up. To our knowledge, no other occurrence of c.617G>A in individuals affected with Severe Combined Immunodeficiency Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690335	SCV000818017	uncertain significance	Immunodeficiency 104	2022-08-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 206 of the IL7R protein (p.Arg206Gln). This variant is present in population databases (rs193922644, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with IL7R-related conditions. ClinVar contains an entry for this variant (Variation ID: 36395). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IL7R 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.