NM_001099857.5(IKBKG):c.931G>A (p.Asp311Asn) AND Ectodermal dysplasia and immunodeficiency 1

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 12, 2016
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:: RCV000589891.2

Allele description [Variation Report for NM_001099857.5(IKBKG):c.931G>A (p.Asp311Asn)]

NM_001099857.5(IKBKG):c.931G>A (p.Asp311Asn)

Gene:

IKBKG:inhibitor of nuclear factor kappa B kinase regulatory subunit gamma [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq28

Genomic location:

Preferred name:

NM_001099857.5(IKBKG):c.931G>A (p.Asp311Asn)

HGVS:

NC_000023.11:g.154563577G>A
NG_009896.1:g.26334G>A
NM_001099856.6:c.1135G>A
NM_001099857.5:c.931G>AMANE SELECT
NM_001145255.4:c.634G>A
NM_001321396.3:c.931G>A
NM_001321397.3:c.928G>A
NM_001377312.1:c.931G>A
NM_001377313.1:c.928G>A
NM_001377314.1:c.775G>A
NM_001377315.1:c.562G>A
NM_003639.4:c.931G>A
NP_001093326.2:p.Asp379Asn
NP_001093327.1:p.Asp311Asn
NP_001138727.1:p.Asp212Asn
NP_001308325.1:p.Asp311Asn
NP_001308326.1:p.Asp310Asn
NP_001364241.1:p.Asp311Asn
NP_001364242.1:p.Asp310Asn
NP_001364243.1:p.Asp259Asn
NP_001364244.1:p.Asp188Asn
NP_003630.1:p.Asp311Asn
LRG_70t1:c.931G>A
LRG_70:g.26334G>A
NC_000023.10:g.153791792G>A
NM_003639.3:c.931G>A
NR_165197.1:n.800G>A
Q9Y6K9:p.Asp311Asn

Protein change:

D188N

Links:

UniProtKB: Q9Y6K9#VAR_011323; UniProtKB/Swiss-Prot: VAR_011323; dbSNP: rs179363867

NCBI 1000 Genomes Browser:

rs179363867

Molecular consequence:

NM_001099856.6:c.1135G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099857.5:c.931G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001145255.4:c.634G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001321396.3:c.931G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001321397.3:c.928G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001377312.1:c.931G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001377313.1:c.928G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001377314.1:c.775G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001377315.1:c.562G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003639.4:c.931G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_165197.1:n.800G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Ectodermal dysplasia and immunodeficiency 1 (EDAID1)
Synonyms:: Ectodermal dysplasia, anhidrotic, with immunodeficiency, osteopetrosis, and lymphedema; ECTODERMAL DYSPLASIA AND IMMUNE DEFICIENCY 1; Hyper-IgM immunodeficiency, X-linked, with hypohidrotic ectodermal dysplasia; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0020740; MedGen: C1846008; Orphanet: 238468; Orphanet: 98813; OMIM: 300291

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000698207	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Dec 12, 2016)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 16818673, 16532398, 18851874, 16950813, 24682681, 21622647, 26117626, 15833888, 17072331 LabCorp Variant Classification Summary - May 2015.docx Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000698207

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Dec 12, 2016)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx

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

Citations

PubMed

X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production.

Filipe-Santos O, Bustamante J, Haverkamp MH, Vinolo E, Ku CL, Puel A, Frucht DM, Christel K, von Bernuth H, Jouanguy E, Feinberg J, Durandy A, Senechal B, Chapgier A, Vogt G, de Beaucoudrey L, Fieschi C, Picard C, Garfa M, Chemli J, Bejaoui M, Tsolia MN, et al.

J Exp Med. 2006 Jul 10;203(7):1745-59. Epub 2006 Jul 3.

PubMed [citation]

PMID:: 16818673
PMCID:: PMC2118353

The NEMO mutation creating the most-upstream premature stop codon is hypomorphic because of a reinitiation of translation.

Puel A, Reichenbach J, Bustamante J, Ku CL, Feinberg J, Döffinger R, Bonnet M, Filipe-Santos O, de Beaucoudrey L, Durandy A, Horneff G, Novelli F, Wahn V, Smahi A, Israel A, Niehues T, Casanova JL.

Am J Hum Genet. 2006 Apr;78(4):691-701. Epub 2006 Feb 15.

PubMed [citation]

PMID:: 16532398
PMCID:: PMC1424680

See all PubMed Citations (9)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000698207.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

Variant summary: The IKBKG c.931G>A (p.Asp311Asn) variant involves the alteration of a conserved nucleotide and is located in the NF-kappa-B essential modulator NEMO, CC2-LZ domain of the protein. 3/4 in silico tools predict a damaging outcome for this variant. The frequency this variant in population control cohorts from ExAC or NHLBI ESP is not available due to lack of coverage of this chromosomal region. This variant has been reported in at least two EDA-ID patients in literature and was absent in the tested 200 control chromosomes (Doffinger_2001, Haverkamp_2014). Functional studies showed that the mutant D311N disrupts monoubiquitin, K63-linked, and linear polyubiquitin binding without affecting the protein folding or total amount of protein production (Hubean_2011). The variant was also shown to cause an impaired cytokine (IL-12) production. IKBKG can function as an intermediary in the NF-kappaB signal transduction through the recuitment of the IKK complex at the occupied cytokine receptors. The variant D311N impairs recognition of ubiquitnated proteins such as receptor interacting protein 1, RIP1 by IKBKG and thus the recruitment of the IKK complex to TNF-R1 (Fusco_2008). The residue p.D311 is highly conserved and another missense change at this residue p.D311G was found in a HED-IP patient and the variant was found to be functionally compromised (Hubean_2011), further supporting the pathogenicity of the variant of interest. Taken together, this variant is currently classified as likely 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

Last Updated: Sep 29, 2024

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