VCV000430907.11 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 430907 Accession: VCV000430907.11

Type and length

Duplication, 1 bp

Location

Cytogenetic: 4q24 4: 102582929-102582930 (GRCh38) [ NCBI UCSC ] 4: 103504086-103504087 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 9, 2018	Feb 20, 2024	Sep 11, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_003998.4:c.904dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003989.2:p.Ser302fs	frameshift
NM_001165412.2:c.901dup	NP_001158884.1:p.Ser301fs	frameshift
NM_001319226.2:c.901dup	NP_001306155.1:p.Ser301fs	frameshift
NM_003998.3:c.904dupT
NC_000004.12:g.102582934dup
NC_000004.11:g.103504091dup
NG_050628.1:g.86606dup
LRG_1316:g.86606dup
LRG_1316t1:c.904dup	LRG_1316p1:p.Ser302fs

... more HGVS ... less HGVS

Protein change

S302fs, S301fs

Other names

Canonical SPDI

NC_000004.12:102582929:TTTTT:TTTTTT

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA3026009 dbSNP: rs773694113 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
NFKB1		-	-	GRCh38 GRCh37	695	739

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Immunodeficiency, common variable, 12	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Sep 3, 2021	RCV000611708.8
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Sep 11, 2023	RCV000788230.6
Inherited Immunodeficiency Diseases	Likely pathogenic (1)	criteria provided, single submitter	Jan 1, 2019	RCV001027605.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Immunodeficiency, common variable, 12 Affected status: yes Allele origin: germline	Department of Immunology, University Hospital Southampton NHSFT Accession: SCV000583982.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Publications: PubMed (1) PubMed: 29077208
Likely pathogenic (Jun 01, 2017)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Blueprint Genetics Accession: SCV000927273.1 First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019 Comment: Patient analyzed with Primary Immunodeficiency Panel
Likely pathogenic (Jan 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Inherited Immunodeficiency Diseases Affected status: yes Allele origin: germline	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV001190177.1 First in ClinVar: Mar 26, 2020 Last updated: Mar 26, 2020	Clinical Features: Abnormality of B cell number (present) , Alopecia (present) , IgG deficiency (present) , Splenomegaly (present)
Likely pathogenic (Jan 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Immunodeficiency, common variable, 12 Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001441028.1 First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020
Pathogenic (Sep 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Immunodeficiency, common variable, 12 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002018328.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Sep 11, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002236344.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024	Publications: PubMed (4) PubMed: 29077208‚ 29477724‚ 31803180‚ 26279205 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 430907). This premature translational stop signal … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 430907). This premature translational stop signal has been observed in individual(s) with common variable immunodeficiency or primary immunodeficiency (PMID: 29077208, 29477724, 31803180). This variant is present in population databases (rs773694113, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Ser302Phefs*7) in the NFKB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NFKB1 are known to be pathogenic (PMID: 26279205, 29477724). (less)
Pathogenic (Oct 19, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Immunodeficiency, common variable, 12 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002767156.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (2) PubMed: 29077208‚ 29477724 Comment: 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 … (more) 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 (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 430907). This premature translational stop signal has been observed in individual(s) with common variable immunodeficiency or primary immunodeficiency (PMID: 29077208, 29477724, 31803180). This variant is present in population databases (rs773694113, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Ser302Phefs*7) in the NFKB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NFKB1 are known to be pathogenic (PMID: 26279205, 29477724).

Comment:

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

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Late-Onset Antibody Deficiency Due to Monoallelic Alterations in NFKB1.	Schröder C	Frontiers in immunology	2019	PMID: 31803180
Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans.	Tuijnenburg P	The Journal of allergy and clinical immunology	2018	PMID: 29477724
Clinical efficacy of a next-generation sequencing gene panel for primary immunodeficiency diagnostics.	Rae W	Clinical genetics	2018	PMID: 29077208
Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency.	Fliegauf M	American journal of human genetics	2015	PMID: 26279205

Text-mined citations for rs773694113 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs773694113 ...