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NM_000629.3(IFNAR1):c.1440+331_*239del AND Immunodeficiency 106, susceptibility to viral infections

Germline classification:
risk factor (1 submission)
Last evaluated:
Jun 30, 2022
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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:
RCV002260526.1

Allele description [Variation Report for NM_000629.3(IFNAR1):c.1440+331_*239del]

NM_000629.3(IFNAR1):c.1440+331_*239del

Gene:
IFNAR1:interferon alpha and beta receptor subunit 1 [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
21q22.11
Genomic location:
Preferred name:
NM_000629.3(IFNAR1):c.1440+331_*239del
HGVS:
  • NC_000021.9:g.33354114_33355788del
  • NM_000629.3:c.1440+331_*239delMANE SELECT
  • NM_001384498.1:c.1440+331_1658+255del
  • NM_001384499.1:c.1295-1202_*462del
  • NM_001384500.1:c.678+331_*239del
  • NM_001384501.1:c.1425+331_*239del
  • NM_001384502.1:c.978+331_*239del
  • NM_001384503.1:c.1440+331_*239del
  • NM_001384504.1:c.1233+331_*239del
  • NC_000021.8:g.34726420_34728094del
Links:
OMIM: 107450.0006
Molecular consequence:
  • NM_000629.3:c.1440+331_*239del - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001384498.1:c.1440+331_1658+255del - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001384499.1:c.1295-1202_*462del - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001384500.1:c.678+331_*239del - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001384501.1:c.1425+331_*239del - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001384502.1:c.978+331_*239del - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001384503.1:c.1440+331_*239del - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001384504.1:c.1233+331_*239del - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001384498.1:c.1440+331_1658+255del - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:
Immunodeficiency 106, susceptibility to viral infections (IMD106)
Synonyms:
IFNAR1 DEFICIENCY
Identifiers:
MONDO: MONDO:0030970; MedGen: C5677009; OMIM: 619935

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002540208OMIM
no assertion criteria provided
risk factor
(Jun 30, 2022) 		germlineliterature only

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Herpes simplex encephalitis in a patient with a distinctive form of inherited IFNAR1 deficiency.

Bastard P, Manry J, Chen J, Rosain J, Seeleuthner Y, AbuZaitun O, Lorenzo L, Khan T, Hasek M, Hernandez N, Bigio B, Zhang P, Lévy R, Shrot S, Reino EJG, Lee YS, Boucherit S, Aubart M, Gijsbers R, Béziat V, Li Z, Pellegrini S, et al.

J Clin Invest. 2021 Jan 4;131(1). doi:pii: 139980. 10.1172/JCI139980.

PubMed [citation]
PMID:
32960813
PMCID:
PMC7773360

Details of each submission

From OMIM, SCV002540208.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In 2 members (P1 and P2) of a consanguineous Arab family with immunodeficiency-106 (IMD106; 619935), Bastard et al. (2021) identified a homozygous 1,675-bp deletion (chr2.g.34,726,420_34,728,094del, GRCh37) in the IFNAR1 gene that removed intron 10, the coding sequence of exon 11, and 239 basepairs of the 3-prime UTR. The mutation, which was found by analysis of copy number variants and confirmed by Sanger sequencing, segregated with the phenotype in the family. It was not present in multiple public databases, including gnomAD. Analysis of patient cells showed that the deletion resulted in aberrant splicing predicted to generate a protein with a C-terminal truncation lacking residues known to be critical for the interaction of IFNAR1 with TYK2 (176941). Patient-derived fibroblasts showed low levels of IFNAR1 mRNA, suggesting nonsense-mediated mRNA decay, although a truncated protein was expressed on the cell surface. Patient cells showed no signaling response or induction of interferon-stimulated gene (ISG) expression in response to stimulation with IFNA2 (147562) or IFNB (147640). The cellular response to IFNG (147570) was normal. The signaling defects could be rescued by expression of wildtype IFNAR1. Patient cells also showed enhanced susceptibility to infection and increased viral replication when exposed to several viruses, including HSV1 and measles, compared to controls. In vitro functional studies in transfected HEK293 cells showed expression of a mutant protein with a truncated C terminus that was expressed normally at the plasma membrane, but was unable to interact with TYK2. In this family, P1 died of HSV1-associated encephalitis, whereas P2 had a less severe phenotype with recurrent viral infections, suspected to include HSV1 and mumps. P1 received MMR vaccination and experienced only a fever that resolved spontaneously. P2 was not vaccinated with MMR, since a sib (P3) died at 12 months of age after an adverse reaction to MMR vaccination; DNA from P3 was not available. The findings highlighted a critical role for IFNAR1 immunity and the type I interferon response to protect against HSV1 infection in the CNS.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Dec 24, 2022