Submissions for variant NM_000206.3(IL2RG):c.202G>A (p.Glu68Lys)

dbSNP: rs1057520644

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV000638843	SCV004809090	pathogenic	X-linked severe combined immunodeficiency	2024-01-31	reviewed by expert panel	curation	NM_000206.3(IL2RG):c.202G>A is a missense variant predicted to cause substitution of Glutamic Acid by Lysine at amino acid 68 (p.Glu68Lys). The variant is absent in gnomAD v4 (PM2_supporting). Male patient (0.5 pt.) with SCID (0.5 pt.), genome sequencing conducted (1 pt.), Absent CD132 expression (1 pt.), T-B+NK- lymphocyte subset profile (0.5 pt.); total :3.5 pts PMID: 30778343 (PP4_moderate). This variant is found in multiple unrelated affected probands (total pts. >16) (PS4_very strong) (PMIDs: 9058718, 24534054,11129345, 32477911,31456805, 27484032,31031743,30778343). As per the SCID VCEP specifications and the Bayesian interpretation of the ACMG/AMP combining rules, 1 Very Strong,1 Moderate and 1 Supporting criteria results in a Pathogenic classification. In summary, this variant meets the criteria to be classified as Pathogenic for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_supporting,PP4_moderate,PS4_very strong (VCEP specifications version 1).
GeneDx	RCV000427716	SCV000516730	pathogenic	not provided	2021-04-08	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31456805, 28747913, 24534054, 22105576, 8088810, 9058718, 11129345, 30778343, 31031743, 27484032, 10993286, 32477911)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000638843	SCV000760395	pathogenic	X-linked severe combined immunodeficiency	2022-06-13	criteria provided, single submitter	clinical testing	This variant is also known as 216G>A E68K. ClinVar contains an entry for this variant (Variation ID: 379561). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects IL2RG function (PMID: 8088810). For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individuals with X-linked severe combined immunodeficiency (X-SCID) and an individual affected with both West syndrome (WS) and X-SCID (PMID: 8088810, 11129345, 24534054). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 68 of the IL2RG protein (p.Glu68Lys). This variant is not present in population databases (gnomAD no frequency).
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253325	SCV001428985	pathogenic	Combined immunodeficiency, X-linked	2017-01-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000427716	SCV002023155	pathogenic	not provided	2019-01-15	criteria provided, single submitter	clinical testing