Variant: NM_002185.5(IL7R):c.394C>T (p.Pro132Ser)

CA124399

14843 (ClinVar)

Gene: IL7R

Condition: severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-positive, NK cell-positive

Inheritance Mode: Autosomal recessive inheritance

UUID: c582c092-02be-4299-8765-4d2021687dfa

Approved on: 2024-01-24

Published on: 2024-01-24

HGVS expressions

NM_002185.5:c.394C>T
NM_002185.5(IL7R):c.394C>T (p.Pro132Ser)
NC_000005.10:g.35871070C>T
CM000667.2:g.35871070C>T
NC_000005.9:g.35871172C>T
CM000667.1:g.35871172C>T
NC_000005.8:g.35906929C>T
NG_009567.1:g.19182C>T
ENST00000303115.8:c.394C>T
ENST00000303115.7:c.394C>T
ENST00000506850.5:c.394C>T
ENST00000514217.5:c.394C>T
NM_002185.3:c.394C>T
NR_120485.1:n.497C>T
NM_002185.4:c.394C>T
NR_120485.2:n.523C>T
NR_120485.3:n.481C>T

Likely Pathogenic

• Met criteria codes: PP1_Strong PM3 PM2_Supporting PS3_Supporting PP4

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 IL7R Version 1.0.0

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

NM_002185.5(IL7R):c.394C>T is a missense variant predicted to cause substitution of Proline by Serine at amino acid 132 (p.Pro132Ser). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002236 (1/44718) in Admixed American population which is lower than the ClinGen SCID VCEP threshold (<0.00004129) for PM2_Supporting, meeting this criterion (PM2_Supporting). 3 patients (PMID: 11023514) were found homozygous for this mutation (1 pt.) (PM3_met). 2 patients (Pt. 85 and 86) were found homozygous for this mutation in a consanguineous family (PMID : 35482138). 3 patients with SCID (0.5 pt.), genome sequencing conducted (0.5 pt.),T-B+NK+ lymphocyte subset profile (0.25 pt.) (Total : 1.25 pts) (PMID: 11023514,PP4_met). In response to IL-7 stimulation, Jak-3 phosphorylation was markedly reduced in both patient cells as well as in COS cells reconstituted with mutant IL-7R. (PMID: 11023514, PS3_supporting). The variant has been reported to segregate with SCID in 3 affected members from 2 families (PP1_strong). In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant for autosomal recessive severe combined immunodeficiency due to IL7R deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting,PM3_met,PP4_met,PS3_supporting,PP1_strong(VCEP specifications version 1).

Met criteria codes

• PP1_Strong: The variant has been reported to segregate with SCID in 3 affected members from 2 families (PP1_strong).
• PM3: 3 patients (PMID: 11023514) were found homozygous for this mutation (1 pt.) (PM3_met). 2 patients (Pt. 85 and 86) were found homozygous for this mutation in a consanguineous family (PMID : 35482138).
• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002236 (1/44718) in Admixed American population which is lower than the ClinGen SCID VCEP threshold (<0.00004129) for PM2_Supporting, meeting this criterion (PM2_Supporting).
• PS3_Supporting: In response to IL-7 stimulation, Jak-3 phosphorylation was markedly reduced in both patient cells as well as in COS cells reconstituted with mutant IL-7R. (PMID: 11023514, PS3_supporting)
• PP4: 3 patients with SCID (0.5 pt.), genome sequencing conducted (0.5 pt.),T-B+NK+ lymphocyte subset profile (0.25 pt.) (Total : 1.25 pts) (PMID: 11023514,PP4_met).