NM_005534.4(IFNGR2):c.1A>C (p.Met1Leu) AND Immunodeficiency 28

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 10, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001376896.8

Allele description [Variation Report for NM_005534.4(IFNGR2):c.1A>C (p.Met1Leu)]

NM_005534.4(IFNGR2):c.1A>C (p.Met1Leu)

Genes:

LOC119266102:IFNGR2 promoter region [Gene]
IFNGR2:interferon gamma receptor 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

21q22.11

Genomic location:

Preferred name:

NM_005534.4(IFNGR2):c.1A>C (p.Met1Leu)

HGVS:

NC_000021.9:g.33403544A>C
NG_007570.2:g.23552A>C
NG_070955.1:g.1284A>C
NM_001329128.2:c.1A>C
NM_005534.4:c.1A>CMANE SELECT
NP_001316057.1:p.Met1Leu
NP_005525.2:p.Met1Leu
LRG_67:g.23552A>C
NC_000021.8:g.34775850A>C

Protein change:

M1L

Links:

dbSNP: rs1316638883

NCBI 1000 Genomes Browser:

rs1316638883

Molecular consequence:

NM_001329128.2:c.1A>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_005534.4:c.1A>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001329128.2:c.1A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_005534.4:c.1A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Immunodeficiency 28 (IMD28)
Synonyms:: IFNGR2 DEFICIENCY
Identifiers:: MONDO: MONDO:0013953; MedGen: C4013947; Orphanet: 319547; Orphanet: 319574; OMIM: 614889

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001574082	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Feb 10, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31222290, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001574082

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Feb 10, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

Citations

PubMed

A purely quantitative form of partial recessive IFN-γR2 deficiency caused by mutations of the initiation or second codon.

Oleaga-Quintas C, Deswarte C, Moncada-Vélez M, Metin A, Krishna Rao I, Kanık-Yüksek S, Nieto-Patlán A, Guérin A, Gülhan B, Murthy S, Özkaya-Parlakay A, Abel L, Martínez-Barricarte R, Pérez de Diego R, Boisson-Dupuis S, Kong XF, Casanova JL, Bustamante J.

Hum Mol Genet. 2018 Nov 15;27(22):3919-3935. doi: 10.1093/hmg/ddy275. Erratum in: Hum Mol Genet. 2019 Feb 1;28(3):524. doi: 10.1093/hmg/ddy357..

PubMed [citation]

PMID:: 31222290
PMCID:: PMC6216222

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, SCV001574082.6

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

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that disruption of the initiator codon affects IFNGR2 function (PMID: 31222290). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 1066015). Disruption of the initiator codon has been observed in individual(s) with Mendelian susceptibility to mycobacterial disease (MSMD) (PMID: 31222290). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the IFNGR2 mRNA. The next in-frame methionine is located at codon 80.

#	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: Feb 16, 2025

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