Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_002185.5(IL7R):c.353G>A (p.Cys118Tyr)

CA214043

36392 (ClinVar)

Gene: IL7R

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

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 27622bc8-a3f6-4be1-8586-efaffc7e60b2

HGVS expressions

NM_002185.5:c.353G>A

NM_002185.5(IL7R):c.353G>A (p.Cys118Tyr)

NC_000005.10:g.35867437G>A

CM000667.2:g.35867437G>A

NC_000005.9:g.35867539G>A

CM000667.1:g.35867539G>A

NC_000005.8:g.35903296G>A

NG_009567.1:g.15549G>A

ENST00000303115.8:c.353G>A

ENST00000303115.7:c.353G>A

ENST00000506850.5:c.353G>A

ENST00000511031.1:n.487G>A

ENST00000511982.1:c.353G>A

ENST00000514217.5:c.353G>A

NM_002185.3:c.353G>A

NR_120485.1:n.456G>A

NM_002185.4:c.353G>A

NR_120485.2:n.482G>A

NR_120485.3:n.440G>A

Pathogenic

PM2_Supporting PP4_Moderate PM3_Very Strong PP1

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The missense variant NM_002185.5(IL7R):c.353G>A (p.Cys118Tyr) occurs at a low filtering allele frequency of 0.000009610 in gnomAD v2.1.1 (<0.00004129; PM2_Supporting). At least 14 SCID or Omenn syndrome patients have been reported with this variant in 10 publications (PMIDs: 35503492, 34573280, 27593400, 24759676, 16492442,15661025, 34153518, 17827065, 24578017, 27833609). Several have highly specific phenotypes which meet criteria for PP4 (PMIDs: 35503492, 24759676) and one patient (PMID: 27833609) had sufficient information to meet PP4_moderate; this patient fulfilled clinical and immunological parameters for severe combined immunodeficiency (SCID), with at T-B+NK+ subtype, absence of CD127 expression, and reduced f IL-7 induced pSTAT5 (Y694) in T-cells, which together are highly specific for IL7R-related SCID (PP4_moderate). Additionally, the variant has been reported to segregate with SCID in 2 affected family members from family 2 in PMID: 15661025 (PP1). Of the 14 patients, eight patients have been reported homozygous for this variant (PMIDs: 35503492, 34573280, 27593400, 24759676, 16492442,15661025; PM3) and six compound heterozygous; second variants were reported in P19 (PMID: 35503492) and the SCID patient reported in Zago CA et al. (PMID: 24759676) both harboring c.361dup without confirmation of trans phase (classified Pathogenic by the SCID VCEP; 0.5+0.5pt), the patients reported by Tsilifis C et al. (PMID: 34153518) and Butte MJ et al. (PMID: 17827065) both harbor c.379+288G>A confirmed in trans (provisionally classified by the SCID VCEP as VUS; 0.25+0.25pt), Case 1 (PMID: 24578017) has c.83-2A>T without confirmation of trans phase (provisionally classified as Pathogenic by the SCID VCEP; 0.5pt), and the patient reported by Gallego-Bustos F et al. (PMID: 27833609) has c.333T>A confirmed in trans (provisionally classified Likely Pathogenic by the SCID VCEP; 1pt), Total=4pts (PM3_VeryStrong). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_supporting, PM3_VeryStrong, PP1, PP4_moderate. (SCID VCEP specifications version 1.0).

PM2_Supporting

The filtering allele frequency based on the Latino/Admixed American population (upper bound of 95% CI of 2/34488 observed alleles) is 0.000009610 in gnomAD v2.1.1 which is below the SCID-VCEP threshold (<0.00004129) and therefore meets this criterion (PM2_Supporting).

PP4_Moderate

At least 14 SCID or Omenn syndrome patients have been reported with this variant in 10 publications (PMIDs: 35503492, 34573280, 27593400, 24759676, 16492442,15661025, 34153518, 17827065, 24578017, 27833609). Several have highly specific phenotypes which meet criteria for PP4 (PMIDs: 35503492, 24759676) and one patient (PMID: 27833609) had sufficient information to meet PP4_moderate, this patient fulfilled clinical and immunological parameters for severe combined immunodeficiency (SCID), with at T-B+NK+ subtype, absence of CD127 expression, and reduced IL-7 induced pSTAT5 (Y694) in T-cells, which together are highly specific for IL7R-related SCID.

PM3_Very Strong

At least eight patients have been reported homozygous for this variant (PMIDs: 35503492, 34573280, 27593400, 24759676, 16492442,15661025; maximum homozygous contribution to score of 1pt). Additionally, at least six compound heterozygotes have also been reported; second variants were reported in P19 (PMID: 35503492) and the SCID patient reported in Zago CA et al. (PMID: 24759676) both harboring c.361dup without confirmation of trans phase (classified Pathogenic by the SCID VCEP; 0.5+0.5pt), the patients reported by Tsilifis C et al. (PMID: 34153518) and Butte MJ et al. (PMID: 17827065) both harbor c.379+288G>A confirmed in trans (provisionally classified by the SCID VCEP as VUS; 0.25+0.25pt), Case 1 (PMID: 24578017) has c.83-2A>T without confirmation of trans phase (provisionally classified as Pathogenic by the SCID VCEP; 0.5pt), and the patient reported by Gallego-Bustos F et al. (PMID: 27833609) has c.333T>A confirmed in trans (provisionally classified Likely Pathogenic by the SCID VCEP; 1pt), Total=4pts; PM3_VeryStrong

PP1

The variant has been reported to segregate with SCID in 2 affected family members from family 2 in PMID: 15661025 (estimated LOD 0.6; PP1).

Approved on: 2024-01-17

Published on: 2024-01-17

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