Variant: NM_000206.3(IL2RG):c.924G>A (p.Ser308=)

CA516771304

962267 (ClinVar)

Gene: IL2RG

Condition: T-B+ severe combined immunodeficiency due to gamma chain deficiency

Inheritance Mode: X-linked inheritance (recessive (HP:0001419))

UUID: 07c181ec-39f7-4240-9769-369ebae3e95d

Approved on: 2024-01-17

Published on: 2024-01-17

HGVS expressions

NM_000206.3:c.924G>A
NM_000206.3(IL2RG):c.924G>A (p.Ser308=)
NC_000023.11:g.71108277C>T
CM000685.2:g.71108277C>T
NC_000023.10:g.70328127C>T
CM000685.1:g.70328127C>T
NC_000023.9:g.70244852C>T
NG_009088.1:g.8277G>A
NG_021141.1:g.3512G>A
ENST00000374202.7:c.924G>A
ENST00000642473.1:n.1288G>A
ENST00000644022.1:n.1190G>A
ENST00000644708.1:n.1233G>A
ENST00000644911.1:n.1330G>A
ENST00000645266.1:c.924G>A
ENST00000645518.1:c.924G>A
ENST00000646106.1:c.924G>A
ENST00000646505.1:c.924G>A
ENST00000647492.1:c.924G>A
ENST00000276110.6:n.1517G>A
ENST00000374188.7:c.111G>A
ENST00000374202.6:c.924G>A
ENST00000456850.6:c.354G>A
ENST00000482750.5:c.240G>A
ENST00000512747.3:n.1103G>A
NM_000206.2:c.924G>A

Likely Pathogenic

• Met criteria codes: PP4_Moderate PM2_Supporting PP1 PP3 PM4

• Not Met criteria codes: BP7

Expert Panel

Severe Combined Immunodeficiency Disease VCEP

Criteria Specification Information

Criteria Specification: ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for IL2RG Version 1.0.0

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The NM_000206.3(IL2RG):c.924G>A (p.Ser308=) synonymous variant occurs at the final nucleotide of exon 7 and is predicted to impact the splice consensus sequence (SpliceAI score 0.95; varSEAK -64.86 %, class 5; MaxEntScan 8.51-->2.69, -68% change) with loss of the donor splice site (PP3). The variant has been reported to segregate with X-SCID through 3 affected segregations. The mutation was confirmed by Sanger sequencing in patients 1 and 2 (maternal first cousins), as well as their mothers (PMID: 30850927; PP1). Patient 1 is a male (0.5pt) with atypical X-SCID, presenting with persistent cutaneous viral infection. There is a family history of SCID (0.5pt) and the patient was sequenced on a panel of 29 SCID causing genes (0.5pt). Phosphorylation of STAT5 after IL-2 stimulation in T cells exhibited a weaker response (1pt). Together these phenotypes and family history are highly specific for SCID due to gamma chain deficiency (2.5pt; PP4_moderate). Validation of a splicing defect was found in IL2RG mRNA analysis in patients 1 and 2 (PMID: 30850927). Skipping of exon 7 was detected which would cause a frameshift in exon 8 (the final exon) with a stop loss and elongation of the protein by 31 amino acids. Of note, products of non-spliced intron 7, other abnormal splicings, and even normal splicing were also detected (PM4). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for X-linked T-B+ severe combined immunodeficiency due to gamma chain deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_supporting, PM4, PP1, PP3, PP4_moderate. (VCEP specifications version 1).

Met criteria codes

• PP4_Moderate: Patient 1 (PMID: 30850927) is a male (0.5pt) with atypical X-SCID, presenting with persistent cutaneous viral infection. There is a family history of SCID (0.5pt) and the patient was sequenced on a panel of 29 SCID causing genes (1pt). Phosphorylation of STAT5 after IL-2 stimulation in T cells exhibited a weaker response (1pt). Together these phenotypes and family history are highly specific for SCID due to gamma chain deficiency (3pt; PP4_moderate).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
• PP1: The variant has been reported to segregate with X-SCID through 3 affected segregations. The mutation was confirmed by Sanger sequencing in patients 1 and 2 (maternal first cousins), as well as their mothers (PMID: 30850927; PP1).
• PP3: The NM_000206.3(IL2RG):c.924G>A (p.Ser308=) synonymous variant occurs at the final nucleotide of exon 7 and is predicted to impact the splice consensus sequence (SpliceAI score 0.95; varSEAK -64.86 %, class 5; MaxEntScan 8.51-->2.69, -68% change) with loss of the donor splice site (PP3).
• PM4: Validation of a splicing defect was found in IL2RG mRNA analysis in patients 1 and 2 (PMID: 30850927). Skipping of exon 7 was detected which would cause a frameshift in exon 8 (the final exon) with a stop loss and elongation of the protein by 31 amino acids. Of note, products of non-spliced intron 7, other abnormal splicings, and even normal splicing were also detected.

Not Met criteria codes

• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline