Variant: NM_000206.3(IL2RG):c.694G>A (p.Gly232Arg)

CA413495953

633274 (ClinVar)

Gene: IL2RG

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

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

UUID: 4d5db81b-3ff2-40ed-90d8-d96d46fa61ea

Approved on: 2024-01-17

Published on: 2024-01-17

HGVS expressions

NM_000206.3:c.694G>A
NM_000206.3(IL2RG):c.694G>A (p.Gly232Arg)
NC_000023.11:g.71109291C>T
CM000685.2:g.71109291C>T
NC_000023.10:g.70329141C>T
CM000685.1:g.70329141C>T
NC_000023.9:g.70245866C>T
NG_009088.1:g.7263G>A
NG_021141.1:g.2498G>A
ENST00000374202.7:c.694G>A
ENST00000642473.1:n.1058G>A
ENST00000644022.1:n.960G>A
ENST00000644708.1:n.1100G>A
ENST00000644911.1:n.1100G>A
ENST00000645266.1:c.694G>A
ENST00000645518.1:c.694G>A
ENST00000646106.1:c.694G>A
ENST00000646505.1:c.694G>A
ENST00000647492.1:c.694G>A
ENST00000276110.6:n.1287G>A
ENST00000374188.7:c.-23G>A
ENST00000374202.6:c.694G>A
ENST00000456850.6:c.124G>A
ENST00000464642.5:c.562G>A
ENST00000482750.5:c.107G>A
ENST00000512747.3:n.621G>A
NM_000206.2:c.694G>A

Uncertain Significance

• Met criteria codes: PP4 PM2_Supporting

• Not Met criteria codes: PM5 PM1 PS1 PP3

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:c.694G>A variant in IL2RG is a missense variant predicted to cause substitution of glycine by arginine at amino acid 232 (p.Gly232Arg). This variant is not present in gnomAD v2.1.1 and therefore is below the minor allele frequency threshold set by the ClinGen SCID-VCEP for PM2_Supporting (<0.000124). This variant (also known as 708G>A in the literature) has been identified in a male individual with T cell lymphopenia who met WHO criteria for SCID (PMID: 9058718, 8961626) and meets the SCID VCEP's criteria for PP4 (male patient (0.5p) meeting diagnostic criteria for SCID (0.5p) = 1p, PP4 met at regular strength). This variant has also been reported in a second male individual with a reported phenotype of SCID (PMID: 28747913) but who did not meet the SCID VCEP criteria for PP4 due to lack of detailed phenotypic information. This variant does not occur in a known hotspot or well-known functional domain according to the SCID VCEP specifications for IL2RG and therefore PM1 is not met. A different nucleotide change (c.694G>C) that results in the same missense change as (p.Gly232Arg) was reported in a patient with a suspected inborn error of immunity (PMID: 35874699) who did not meet PP4 criteria for SCID. This variant has not yet been classified by the SCID VCEP and therefore PS1 is not met. Two additional variants c.695G>A and c.695G>T resulting in different missense changes at this same codon (p.Gly232Glu and p.Gly232Val, respectively) were reported in individuals with suspected primary immunodeficiencies (PMID: 28359783, 33942430) but neither meets PP4 criteria for SCID. These variants have not yet been classified by the SCID VCEP and therefore PM5 is not met. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_Supporting, PP4. (VCEP specifications version 1).

Met criteria codes

• PP4: Patient 708G>A from PMID: 905871 is male (0.5p) with SCID by WHO criteria diagnosed by either immunologist or geneticist (I think this is good enough to say diagnostic criteria for SCID is met - 0.5p) so this is at least 1p (PP4 met at regular strength). The methods for paper say all patients had T lymphopenia and the majority had normal or elevated B cells but I'm not sure if this is good enough to say the patient with our variant has T-B+ SCID. Also there was no information about Nk cells or panel/exome sequencing so I did not award an additional 0.5p for T-B+NK- lymphocyte profile (note that even if we added this, this patient would then be 1.5p which is still PP4 at regular strength, so it makes no difference). Patient P037 in PMID: 28747913 does not meet PP4 - patient is presumed male (0.5p) and presumably has SCID but no T, B or NK values given and not clear if diagnostic SCID criteria is met (even if diagnostic criteria were met, this would be 0.5p, so this patient would get a maximum of 1p, which could meet PP4 at regular strength, but we already have another patient who meets PP4 at regular strength, so this additional patient would not help us increase the strength of PP4 anyway).
• PM2_Supporting: Variant is absent in gnomAD, therefore it is below threshold for PM2_Supporting set by SCID VCEP for IL2RG (<0.000124)

Not Met criteria codes

• PM5: Two additional variants assessed, each reported in a single proband with suspected PID, but none with a clear SCID phenotype. Variants are likely VUS. Brief summary of each variant (additional details for each variant in PMID evidence notes): A DIFFERENT missense change at this codon p.Gly232Val was identified in a patient with suspected monogenic PID (PMID: 33942430). A DIFFERENT missense change at this codon p.Gly232Glu was identified in a patient with suspected PID (PMID: 28359783).
• PM1: Missense at codon Gly232 - does not affect any of the codons or nucleotides specified by SCID VCEP for hotspot/critical domain - conserved cysteine (C62, C72, C102, C115), CpG dinucleotides (c.684C, c.690C, c.691G, c.868G), WSxWS motif (W237, S238, E239, W240, S241), or transmembrane domain/polar residue (amino acids 263-283). Therefore, PM1 is not met.
• PS1: A DIFFERENT nucleotide change (c.694G>C) that results in the SAME missense change as our variant (p.Gly232Arg) was identified in a patient with suspected IEI (PMID: 35874699) but no clear SCID phenotype. Variant likely VUS. See additional details in PMID evidence notes.
• PP3: as per SCID VCEP's IL2RG specifications, PP3 does not apply to missense variants