NM_002185.5(IL7R):c.361dup (p.Ile121fs) AND Immunodeficiency 104

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Nov 14, 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:: RCV000210421.10

Allele description [Variation Report for NM_002185.5(IL7R):c.361dup (p.Ile121fs)]

NM_002185.5(IL7R):c.361dup (p.Ile121fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

5p13.2

Genomic location:

Preferred name:

NM_002185.5(IL7R):c.361dup (p.Ile121fs)

Other names:

NM_002185.5(IL7R):c.361dup; p.Ile121fs

HGVS:

NC_000005.10:g.35867445dup
NG_009567.1:g.15557dup
NM_002185.5:c.361dupMANE SELECT
NP_002176.2:p.Ile121fs
LRG_74t1:c.361dup
LRG_74:g.15557dup
NC_000005.9:g.35867540_35867541insA
NC_000005.9:g.35867547dup
NM_002185.2:c.361dupA
NM_002185.3:c.361dupA
NR_120485.3:n.448dup

Protein change:

I121fs

Links:

dbSNP: rs869312857

NCBI 1000 Genomes Browser:

rs869312857

Molecular consequence:

NM_002185.5:c.361dup - frameshift variant - [Sequence Ontology: SO:0001589]
NR_120485.3:n.448dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

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
SCV000256762	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	criteria provided, single submitter (Bayer et al. (Clin Exp Immunol 2014))	Pathogenic (Jul 16, 2014)	inherited	research	PubMed (1) [See all records that cite this PMID]
SCV001334109	Department of Molecular and Human Genetics, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 16, 2020)	inherited	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 32576985
SCV001584355	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 29, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 21664875, 26123418, 24759676, 25046553, 28492532
SCV002813979	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 26, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004102833	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen SCID ACMG Specifications IL7R V1.0.0)	Pathogenic (Nov 14, 2023)	germline	curation	Citation Link

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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
not provided	inherited	yes	1	1	not provided	not provided	yes	clinical testing, research
not provided	inherited	no	1	not provided	not provided	not provided	yes	research
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

CNVs cause autosomal recessive genetic diseases with or without involvement of SNV/indels.

Yuan B, Wang L, Liu P, Shaw C, Dai H, Cooper L, Zhu W, Anderson SA, Meng L, Wang X, Wang Y, Xia F, Xiao R, Braxton A, Peacock S, Schmitt E, Ward PA, Vetrini F, He W, Chiang T, Muzny D, Gibbs RA, et al.

Genet Med. 2020 Oct;22(10):1633-1641. doi: 10.1038/s41436-020-0864-8. Epub 2020 Jun 24.

PubMed [citation]

PMID:: 32576985
PMCID:: PMC8445517

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

See all PubMed Citations (7)

Details of each submission

From Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine, SCV000256762.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	yes	research	PubMed (1)
2	not provided	1	not provided	yes	research	PubMed (1)

Description

Observed in trans with a pathogenic exon 3 deletion

Description

segregates with the phenotype in an affected family

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	discovery		1	not provided	1	not provided
2	inherited	no	not provided	not provided	discovery		1	not provided	not provided	not provided

From Department of Molecular and Human Genetics, Baylor College of Medicine, SCV001334109.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

in trans with IL7R exon 3 deletion

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001584355.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Ile121Asnfs*8) 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). This variant is present in population databases (rs781000678, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with clinical features of severe combined immunodeficiency (PMID: 24759676, 25046553). ClinVar contains an entry for this variant (Variation ID: 224841). For these reasons, this variant has been classified as Pathogenic.

#	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 Fulgent Genetics, Fulgent Genetics, SCV002813979.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	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, SCV004102833.1

#	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.361dup (p.Ile121AsnfsTer8) frameshift variant in exon 3 creates a premature stop codon in exon 4/5 (upstream of the final 50 nucleotides), which is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in several SCID patients (PMIDs: 35503492, 24759676, 32765500, 28436970, 25046553), at least one of whom was reported with a highly specific phenotype; the diagnosis of SCID was made by criteria of the Primary Immune Deficiency Treatment Consortium in this patient with a T−BlowNK+ (0 CD3+ cells/mm, 300 B cells/mm3, 450 NK cells/mm3) lymphocyte subset profile (PMID: 35503492; PP4). The filtering allele frequency based on the European (non-Finnish) population (upper bound of 95% CI of 9/128422 observed alleles) is 0.00002867 in gnomAD v2.1.1 which is below the SCID-VCEP threshold (<0.00004129) and therefore meets this criterion (PM2_Supporting). 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: PVS1, PM2_supporting, PP4. (VCEP specifications version 1).

#	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: Sep 29, 2024

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