rs193922641

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 6 ACMG points: 6P and 0B. PP4_ModeratePP1PM3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA214043/MONDO:0012163/119

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

IL7R
NM_002185.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:6

Conservation

PhyloP100: 1.57

Variant links:

Genes affected

IL7R (HGNC:6024): (interleukin 7 receptor) The protein encoded by this gene is a receptor for interleukin 7 (IL7). The function of this receptor requires the interleukin 2 receptor, gamma chain (IL2RG), which is a common gamma chain shared by the receptors of various cytokines, including interleukins 2, 4, 7, 9, and 15. This protein has been shown to play a critical role in V(D)J recombination during lymphocyte development. Defects in this gene may be associated with severe combined immunodeficiency (SCID). Alternatively spliced transcript variants have been found. [provided by RefSeq, Dec 2015]

IL7R links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 6 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL7R	NM_002185.5 link	c.353G>A	p.Cys118Tyr	missense_variant	Exon 3 of 8	ENST00000303115.8	NP_002176.2	P16871-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL7R	ENST00000303115.8 link	c.353G>A	p.Cys118Tyr	missense_variant	Exon 3 of 8	1	NM_002185.5	ENSP00000306157.3		P16871-1

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151962

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250510

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135422

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1460758

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726712

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000900

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000395

AC:

AN:

151962

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74222

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000478

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Immunodeficiency 104

Pathogenic:4

Jun 10, 2022

DASA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.353G>A;p.(Cys118Tyr) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 36392; PMID: 15661025; 16492442; 17827065; 18403192; 24759676; 27833609) - PS4. The variant is present at low allele frequencies population databases (rs193922641– gnomAD 0.0003948%; ABraOM 0.001708 frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Cys118Tyr) was detected in trans with a Pathogenic variant (PMID: 24759676) - PM3. In summary, the currently available evidence indicates that the variant is Likely Pathogenic -

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 118 of the IL7R protein (p.Cys118Tyr). This variant is present in population databases (rs193922641, gnomAD 0.006%). This missense change has been observed in individuals with severe combined immunodeficiency (PMID: 15661025, 16492442, 17827065, 24759676, 27833609). It has also been observed to segregate with disease in related individuals. This variant is also known as 375G>A (p.C118Y). ClinVar contains an entry for this variant (Variation ID: 36392). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt IL7R protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Oct 10, 2023

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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). -

Dec 01, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS4 strong, PM2 moderate, PM3 strong, PP4 supporting -

Severe combined immunodeficiency disease

Pathogenic:1

Sep 21, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: IL7R c.353G>A (p.Cys118Tyr) results in a non-conservative amino acid change located in the IL-7Ralpha, fibronectin type III domain (IPR040997) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250650 control chromosomes (gnomAD and publication data). c.353G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Severe Combined Immunodeficiency Syndrome/Omenn Syndrome (e.g. Giliani_2005, Giliani_2006, Butte_2007, Zago_2014, Gallego-Bustos_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17827065, 27833609, 15661025, 16492442, 24759676). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Oct 27, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(C98Y); This variant is associated with the following publications: (PMID: 16492442, 17827065, 24759676, 31589614, 35503492, 34573280, 34598035, 15661025, 35601409, 19141282, 24578017, 27833609) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Uncertain

0.086

BayesDel_noAF

Uncertain

0.060

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.25

T;.;.

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.58

T;T;T

M_CAP

Benign

0.017

MetaRNN

Uncertain

0.61

D;D;D

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.2

M;M;.

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-4.4

D;D;D

REVEL

Uncertain

0.44

Sift

Benign

0.29

T;T;T

Sift4G

Benign

0.17

T;T;D

Polyphen

0.40

B;.;.

Vest4

0.61

MVP

0.88

MPC

0.017

ClinPred

0.68

GERP RS

3.8

Varity_R

0.38

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over