NM_002185.5(IL7R):c.152C>T (p.Ser51Leu) AND Immunodeficiency 104

Germline classification:: Likely benign (3 submissions)
Last evaluated:: Jan 10, 2024
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:: RCV000819281.17

Allele description [Variation Report for NM_002185.5(IL7R):c.152C>T (p.Ser51Leu)]

NM_002185.5(IL7R):c.152C>T (p.Ser51Leu)

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.152C>T (p.Ser51Leu)

Other names:

NM_002185.5(IL7R):c.152C>T; p.Ser51Leu

HGVS:

NC_000005.10:g.35860921C>T
NG_009567.1:g.9033C>T
NM_002185.5:c.152C>TMANE SELECT
NP_002176.2:p.Ser51Leu
LRG_74:g.9033C>T
NC_000005.9:g.35861023C>T
NM_002185.3:c.152C>T
NR_120485.3:n.239C>T

Protein change:

S51L

Links:

dbSNP: rs138482569

NCBI 1000 Genomes Browser:

rs138482569

Molecular consequence:

NM_002185.5:c.152C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_120485.3:n.239C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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

Recent activity

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MULTISPECIES: MarR family transcriptional regulator [Anoxybacillus]
MULTISPECIES: MarR family transcriptional regulator [Anoxybacillus]
gi|2461866589|ref|WP_275900496.1|

Protein
large ribosomal subunit protein eL27 [Homo sapiens]
large ribosomal subunit protein eL27 [Homo sapiens]
gi|1169640552|ref|NP_001336851.1|

Protein
Homo sapiens ribosomal protein L27 (RPL27), transcript variant 2, mRNA
Homo sapiens ribosomal protein L27 (RPL27), transcript variant 2, mRNA
gi|1677539467|ref|NM_001349921.2|

Nucleotide
Homo sapiens aspartate beta-hydroxylase (ASPH), transcript variant 24, mRNA
Homo sapiens aspartate beta-hydroxylase (ASPH), transcript variant 24, mRNA
gi|2328705179|ref|NM_001413855.1|

Nucleotide
Homo sapiens ETS variant transcription factor 4 (ETV4), transcript variant 1, mR...
Homo sapiens ETS variant transcription factor 4 (ETV4), transcript variant 1, mRNA
gi|1616592608|ref|NM_001986.4|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000959931	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Jan 18, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001316509	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jan 12, 2018)	germline	clinical testing	Citation Link,
SCV004242290	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen SCID ACMG Specifications IL7R V1.0.0)	Likely benign (Jan 10, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000959931

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely benign
(Jan 18, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001316509

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Jan 12, 2018)

germline

clinical testing

Citation Link,

SCV004242290

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen SCID ACMG Specifications IL7R V1.0.0)

Likely benign
(Jan 10, 2024)

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000959931.6

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV001316509.1

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

#	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, SCV004242290.1

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

Description

NM_002185.5(IL7R):c.152C>T is a missense variant predicted to cause substitution of Serine by Leucine at amino acid 51 (p.Ser51Leu). The filtering allele frequency (the lower threshold of the 95% CI of 110/74978) of the c.152C>T variant in IL7R is 0.001270 for African/African American chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00126) for BS1, and therefore meets this criterion (BS1). To our knowledge, this variant has not been reported in the literature in individuals affected with IL7R-related conditions or in functional studies. As per SCID VCEP specifications, 1 Strong criteria is enough to reach Likely Benign classification. In summary, this variant meets the criteria to be classified as a Likely Benign 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: BS1 (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: Oct 20, 2024

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