Submissions for variant NM_002185.5(IL7R):c.419G>A (p.Arg140Gln)

gnomAD frequency: 0.00019  dbSNP: rs200373233

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001064354	SCV000457144	uncertain significance	Immunodeficiency 104	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000493702	SCV000582097	uncertain significance	not provided	2017-05-11	criteria provided, single submitter	clinical testing	The R140Q variant has been observed in the heterozygous state previously in an individual with SCID (Broides et al., 2006). However, the patient exhibited normal expression levels of the IL7R protein, had a co-occurring genomic deletion, and his heterozygous father was unaffected. The variant is observed in 21/16498 (0.13%) alleles from individuals of South Asian background in the ExAC dataset (Lek et al., 2016). R140Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001064354	SCV001229251	uncertain significance	Immunodeficiency 104	2022-08-09	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 140 of the IL7R protein (p.Arg140Gln). This variant is present in population databases (rs200373233, gnomAD 0.1%). 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: 353264). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited	RCV001064354	SCV002061917	uncertain significance	Immunodeficiency 104		criteria provided, single submitter	clinical testing	The variant is predicted to be damaging by PolyPhen2 and the residue is conserved across species. The amino acid change p.Arg140Gln in IL7R is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is present in 0.03% alleles in heterozygous state. It is not observed in homozygous state. Hence it has been classified as Uncertain Significance.