NM_002185.5(IL7R):c.265C>T (p.Gln89Ter) AND Immunodeficiency 104

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Oct 10, 2023
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001869366.6

Allele description [Variation Report for NM_002185.5(IL7R):c.265C>T (p.Gln89Ter)]

NM_002185.5(IL7R):c.265C>T (p.Gln89Ter)

Gene:

IL7R:interleukin 7 receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5p13.2

Genomic location:

Preferred name:

NM_002185.5(IL7R):c.265C>T (p.Gln89Ter)

Other names:

NM_002185.5(IL7R):c.265C>T; p.Gln89Ter

HGVS:

NC_000005.10:g.35867349C>T
NG_009567.1:g.15461C>T
NM_002185.5:c.265C>TMANE SELECT
NP_002176.2:p.Gln89Ter
LRG_74:g.15461C>T
NC_000005.9:g.35867451C>T
NC_000005.9:g.35867451C>T
NM_002185.3:c.265C>T
NR_120485.3:n.352C>T
p.Gln89X

Protein change:

Q89*

Links:

dbSNP: rs141698985

NCBI 1000 Genomes Browser:

rs141698985

Molecular consequence:

NR_120485.3:n.352C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_002185.5:c.265C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Immunodeficiency 104
Synonyms:: SCID, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE, B CELL-POSITIVE, NK CELL-POSITIVE; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-positive, NK cell-positive; IMMUNODEFICIENCY 104, SEVERE COMBINED; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012163; MedGen: C5676890; OMIM: 608971

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002234621	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 9, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21664875, 26123418, 28492532
SCV004098871	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen SCID ACMG Specifications IL7R V1.0.0)	Likely pathogenic (Oct 10, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002234621

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 9, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004098871

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen SCID ACMG Specifications IL7R V1.0.0)

Likely pathogenic
(Oct 10, 2023)

germline

curation

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Clinical and immunological manifestations of patients with atypical severe combined immunodeficiency.

Felgentreff K, Perez-Becker R, Speckmann C, Schwarz K, Kalwak K, Markelj G, Avcin T, Qasim W, Davies EG, Niehues T, Ehl S.

Clin Immunol. 2011 Oct;141(1):73-82. doi: 10.1016/j.clim.2011.05.007. Epub 2011 May 30. Review.

PubMed [citation]

PMID:: 21664875

Hypomorphic interleukin-7 receptor α-chain mutations and T-cell deficiency: a delay in diagnosis.

Leiding JW, Sriaroon P, Ly JM, Petrovic A, Howard DL, Shamblott M, Kuehn HS, Fleisher TA.

Ann Allergy Asthma Immunol. 2015 Jul;115(1):1-3. doi: 10.1016/j.anai.2015.04.024. No abstract available.

PubMed [citation]

PMID:: 26123418

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002234621.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 804345). This variant has not been reported in the literature in individuals affected with IL7R-related conditions. This variant is present in population databases (rs141698985, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Gln89*) in the IL7R gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IL7R are known to be pathogenic (PMID: 21664875, 26123418).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen, SCV004098871.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The NM_002185.5(IL7R):c.265C>T (p.Gln89Ter) variant in IL7R is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 3/8, which is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The filtering allele frequency based on the European (non-Finnish) population (upper bound of 95% CI of 3/113430 alleles) is 0.000007030 in gnomAD v2.1.1, which is below the SCID-VCEP threshold (<0.00004129; PM2_Supporting). This variant has been reported in ClinVar and LOVD without patient information; however, it has not been reported in the literature to our knowledge. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1, PM2_supporting (SCID VCEP specifications version 1.0).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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