Submissions for variant NM_000206.3(IL2RG):c.325G>A (p.Glu109Lys)

gnomAD frequency: 0.00059  dbSNP: rs17875899

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV000638846	SCV004102803	benign	X-linked severe combined immunodeficiency	2023-11-14	reviewed by expert panel	curation	The NM_000206.3(IL2RG):c.325G>A (p.Glu109Lys) is a missense variant that has been reported in ClinVar, without patient information, however it has not been reported in the literature to our knowledge. It occurs at an intermediate allele frequency, with a popmax filtering allele frequency in gnomAD v2.1.1 of 0.0006719 (based on 74/92629 alleles in the non-Finnish European population) which is below the SCID VCEP established threshold of >0.00249 for BS1 and above the PM2 threshold of <0.000124. However, the highest MAF is in the Finnish population at 0.004561 (85/18638 alleles, 28 hemizygotes and 1 homozygote) which is above the SCID VCEP established threshold of >0.00249. As this population is not known to have a higher prevalence of this is considered to meet BS1. Sixty-two adult hemizygous males with this variant are present in the gnomADv2.1.1 dataset as well as a homozygous female (BS2). In summary, this variant is classified as Benign. Criteria applied: BS1, BS2 (VCEP specifications version 1).
Illumina Laboratory Services, Illumina	RCV000638846	SCV000482706	benign	X-linked severe combined immunodeficiency	2018-01-12	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000610972	SCV000722791	likely benign	not specified	2017-09-08	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000638846	SCV000760398	benign	X-linked severe combined immunodeficiency	2024-01-27	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001702634	SCV001932200	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000610972	SCV001965180	benign	not specified		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000638846	SCV002087232	likely benign	X-linked severe combined immunodeficiency	2019-12-09	no assertion criteria provided	clinical testing