Submissions for variant NM_000206.3(IL2RG):c.395T>A (p.Leu132His)

dbSNP: rs2092261278

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002026875	SCV002307679	likely pathogenic	X-linked severe combined immunodeficiency	2021-06-16	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Leu132 amino acid residue in IL2RG. Other variant(s) that disrupt this residue have been observed in individuals with IL2RG-related conditions (PMID: 9633906, Invitae), which suggests that this may be a clinically significant amino acid residue. 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 IL2RG protein function. This variant has been observed in individual(s) with clinical features of severe combined immunodeficiency (SCID) (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with histidine at codon 132 of the IL2RG protein (p.Leu132His). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and histidine.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003491018	SCV004241436	uncertain significance	not specified	2023-12-14	criteria provided, single submitter	clinical testing	Variant summary: IL2RG c.395T>A (p.Leu132His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183486 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.395T>A in individuals affected with X-Linked Severe Combined Immunodeficiency and no experimental evidence demonstrating its impact on protein function have been reported in the literature. One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic, citing internal data. Based on the evidence outlined above, the variant was classified as uncertain significance.