NM_003998.4(NFKB1):c.904dup (p.Ser302fs) AND Immunodeficiency, common variable, 12

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Sep 3, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000611708.8

Allele description [Variation Report for NM_003998.4(NFKB1):c.904dup (p.Ser302fs)]

NM_003998.4(NFKB1):c.904dup (p.Ser302fs)

Gene:

NFKB1:nuclear factor kappa B subunit 1 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

4q24

Genomic location:

Preferred name:

NM_003998.4(NFKB1):c.904dup (p.Ser302fs)

HGVS:

NC_000004.12:g.102582934dup
NG_050628.1:g.86606dup
NM_001165412.2:c.901dup
NM_001319226.2:c.901dup
NM_003998.4:c.904dupMANE SELECT
NP_001158884.1:p.Ser301fs
NP_001306155.1:p.Ser301fs
NP_003989.2:p.Ser302fs
LRG_1316t1:c.904dup
LRG_1316:g.86606dup
LRG_1316p1:p.Ser302fs
NC_000004.11:g.103504086_103504087insT
NC_000004.11:g.103504091dup
NM_003998.3:c.904dup
NM_003998.3:c.904dupT

Protein change:

S301fs

Links:

dbSNP: rs773694113

NCBI 1000 Genomes Browser:

rs773694113

Molecular consequence:

NM_001165412.2:c.901dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001319226.2:c.901dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_003998.4:c.904dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Immunodeficiency, common variable, 12 (CVID12)
Synonyms:: NFKB1 DEFICIENCY; IMMUNODEFICIENCY, COMMON VARIABLE, 12, WITH AUTOIMMUNITY
Identifiers:: MONDO: MONDO:0014697; MedGen: C4225277; Orphanet: 1572; OMIM: 616576

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000583982	Department of Immunology, University Hospital Southampton NHSFT	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 29077208
SCV001441028	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 1, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002018328	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 3, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002767156	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 19, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29077208, 29477724, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinical efficacy of a next-generation sequencing gene panel for primary immunodeficiency diagnostics.

Rae W, Ward D, Mattocks C, Pengelly RJ, Eren E, Patel SV, Faust SN, Hunt D, Williams AP.

Clin Genet. 2018 Mar;93(3):647-655. doi: 10.1111/cge.13163. Epub 2018 Feb 2.

PubMed [citation]

PMID:: 29077208

Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans.

Tuijnenburg P, Lango Allen H, Burns SO, Greene D, Jansen MH, Staples E, Stephens J, Carss KJ, Biasci D, Baxendale H, Thomas M, Chandra A, Kiani-Alikhan S, Longhurst HJ, Seneviratne SL, Oksenhendler E, Simeoni I, de Bree GJ, Tool ATJ, van Leeuwen EMM, Ebberink EHTM, Meijer AB, et al.

J Allergy Clin Immunol. 2018 Oct;142(4):1285-1296. doi: 10.1016/j.jaci.2018.01.039. Epub 2018 Mar 2.

PubMed [citation]

PMID:: 29477724
PMCID:: PMC6148345

See all PubMed Citations (3)

Details of each submission

From Department of Immunology, University Hospital Southampton NHSFT, SCV000583982.1

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

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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001441028.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002018328.3

#	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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002767156.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with common variable immunodeficiency 12 (MIM#616576). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 29477724). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported as pathogenic in individuals with common variable immunodeficiency (ClinVar). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in patients with common variable immunodeficiency (ClinVar, PMID: 29077208, 29477724). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting Pathogenic, (I) – Information, (SB) – Supporting Benign

#	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

ClinVar

Relating variation to medicine