VCV000426990.49 - ClinVar

NM_000265.7(NCF1):c.579G>A (p.Trp193Ter)

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.

(13)

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_000265.7(NCF1):c.579G>A (p.Trp193Ter)

Variation ID: 426990 Accession: VCV000426990.49

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q11.23 7: 74783529 (GRCh38) [ NCBI UCSC ] 7: 74197872 (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	May 22, 2017	Oct 20, 2024	Mar 14, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000265.7:c.579G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000256.4:p.Trp193Ter	nonsense
NC_000007.14:g.74783529G>A
NC_000007.13:g.74197872G>A
NG_009078.2:g.14566G>A
NG_042249.1:g.49693G>A
LRG_87:g.14566G>A
LRG_87t1:c.579G>A	LRG_87p1:p.Trp193Ter

... more HGVS ... less HGVS

Protein change

W193*

Other names

Canonical SPDI

NC_000007.14:74783528:G:A

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.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038

The Genome Aggregation Database (gnomAD) 0.00054

Exome Aggregation Consortium (ExAC) 0.00065

The Genome Aggregation Database (gnomAD), exomes 0.00069

Links

ClinGen: CA4298223 dbSNP: rs145360423 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.
NCF1		No evidence available	No evidence available	GRCh38 GRCh37	4	118
LOC106029312	-	-	-	GRCh38	-	112

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.
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 17, 2022	RCV000489061.31
Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 1	Pathogenic/Likely pathogenic (7)	criteria provided, multiple submitters, no conflicts	Mar 14, 2024	RCV000763595.16
Chronic granulomatous disease due to deficiency of NCF-1	Pathogenic (1)	no assertion criteria provided	Jan 6, 2020	RCV000991165.2
Chronic granulomatous disease	Pathogenic (1)	criteria provided, single submitter	Sep 9, 2022	RCV002298619.2

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 (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 1 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000894439.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Oct 23, 2018)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV000928014.1 First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019 Comment: Patient analyzed with Primary Immunodeficiency Panel
Pathogenic (Sep 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 1 Affected status: yes Allele origin: germline	3billion Accession: SCV002573154.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (1) PubMed: 11920901 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.064%). Stop-gained (nonsense) is predicted to result in … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.064%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. A pathogenic variant is reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000426990 / PMID: 11920901). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Epistaxis (present) , Melena (present) , Ecchymosis (present) , Cerebral hemorrhage (present) , Brain abscess (present) , Lymphadenitis (present) , Cervical lymphadenopathy (present) , Generalized … (more) Epistaxis (present) , Melena (present) , Ecchymosis (present) , Cerebral hemorrhage (present) , Brain abscess (present) , Lymphadenitis (present) , Cervical lymphadenopathy (present) , Generalized lymphadenopathy (present) , Hepatosplenomegaly (present) , Impaired ADP-induced platelet aggregation (present) , Prolonged bleeding time (present) , Increased mean platelet volume (present) , Neutropenia (present) , Hypochromic microcytic anemia (present) (less)
Pathogenic (Sep 09, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Chronic granulomatous disease Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002598599.1 First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022	Publications: PubMed (2) PubMed: 24446915‚ 33746979 Comment: Variant summary: NCF1 c.579G>A (p.Trp193X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: NCF1 c.579G>A (p.Trp193X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar. The variant allele was found at a frequency of 0.00069 in 250032 control chromosomes (gnomAD). This frequency is not higher than predicted for a pathogenic variant in NCF1 causing Chronic Granulomatous Disease (0.00069 vs 0.0011). c.579G>A has been reported in the literature in multiple individuals affected with Chronic Granulomatous Disease and the variant segregated with disease. These data indicate that the variant is very likely to be associated with disease. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jun 14, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000577593.7 First in ClinVar: May 22, 2017 Last updated: Mar 04, 2023	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 18708296, 31172494, 16972229, 26460255, 25525159, 11920901, 27220316, 27701760, 28886419, 29947158, 29454792, 29331982, 24446915, 30963593, 30487145, 29411231, 31980526, 32736065, 33629196, 34573280, 31589614, 33746979, 35464432, 35112591) (less)
Likely pathogenic (Mar 28, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 1 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002018231.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Feb 01, 2018)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001246654.26 First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Dec 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital Accession: SCV002818131.1 First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004048115.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: The stop gained variant c.579G>A (p.Trp193Ter) in NCF1 gene has previously been reported in homozygous state in multiple patients affected with chronic granulomatous disease (Al-Zadjali … (more) The stop gained variant c.579G>A (p.Trp193Ter) in NCF1 gene has previously been reported in homozygous state in multiple patients affected with chronic granulomatous disease (Al-Zadjali et al. 2015). The variant is novel (not in any individuals) in 1000 Genomes and is present in the gnomAD exomes database with a frequency of 0.07%. This variant has been reported to the ClinVar database as Pathogenic. This variant results in a premature termination codon which is predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease. The nucleotide change in NCF1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Brain abscess (present) , Fever (present) , Cough (present)
Likely pathogenic (Mar 14, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Chronic granulomatous disease 1, autosomal recessive Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV005016566.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024
Pathogenic (Jan 06, 2020)	no assertion criteria provided Method: curation	Chronic granulomatous disease due to deficiency of NCF-1 Affected status: unknown Allele origin: germline	Reproductive Health Research and Development, BGI Genomics Accession: SCV001142369.1 First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020	Comment: NM_000265.4:c.579G>A in the NCF1 gene has an allele frequency of 0.011 in Ashkenazi Jewish subpopulation in the gnomAD database. The NCF1 c.579G>A (p.Trp193) variant results … (more) NM_000265.4:c.579G>A in the NCF1 gene has an allele frequency of 0.011 in Ashkenazi Jewish subpopulation in the gnomAD database. The NCF1 c.579G>A (p.Trp193) variant results in a premature termination codon, predicted to cause a truncated or absent protein due to nonsense mediated decay. This variant has been detected in 13 patients affected with chronic granulomatous disease, all in homozygous states (PMID: 24446915). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PVS1; PM3; PP4. (less)
Pathogenic (Feb 05, 2020)	no assertion criteria provided Method: clinical testing	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 1 Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001469165.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021
Pathogenic (Dec 30, 2017)	no assertion criteria provided Method: curation	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 1 Affected status: yes Allele origin: unknown	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University Accession: SCV000891534.2 First in ClinVar: Mar 24, 2019 Last updated: Jun 23, 2024	Geographic origin: Middle East
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Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.064%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. A pathogenic variant is reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000426990 / PMID: 11920901). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

Variant summary: NCF1 c.579G>A (p.Trp193X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar. The variant allele was found at a frequency of 0.00069 in 250032 control chromosomes (gnomAD). This frequency is not higher than predicted for a pathogenic variant in NCF1 causing Chronic Granulomatous Disease (0.00069 vs 0.0011). c.579G>A has been reported in the literature in multiple individuals affected with Chronic Granulomatous Disease and the variant segregated with disease. These data indicate that the variant is very likely to be associated with disease. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 18708296, 31172494, 16972229, 26460255, 25525159, 11920901, 27220316, 27701760, 28886419, 29947158, 29454792, 29331982, 24446915, 30963593, 30487145, 29411231, 31980526, 32736065, 33629196, 34573280, 31589614, 33746979, 35464432, 35112591)

Comment:

The stop gained variant c.579G>A (p.Trp193Ter) in NCF1 gene has previously been reported in homozygous state in multiple patients affected with chronic granulomatous disease (Al-Zadjali et al. 2015). The variant is novel (not in any individuals) in 1000 Genomes and is present in the gnomAD exomes database with a frequency of 0.07%. This variant has been reported to the ClinVar database as Pathogenic. This variant results in a premature termination codon which is predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease. The nucleotide change in NCF1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

Comment:

NM_000265.4:c.579G>A in the NCF1 gene has an allele frequency of 0.011 in Ashkenazi Jewish subpopulation in the gnomAD database. The NCF1 c.579G>A (p.Trp193*) variant results in a premature termination codon, predicted to cause a truncated or absent protein due to nonsense mediated decay. This variant has been detected in 13 patients affected with chronic granulomatous disease, all in homozygous states (PMID: 24446915). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PVS1; PM3; PP4.

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
Second Report of Chronic Granulomatous Disease in Jordan: Clinical and Genetic Description of 31 Patients From 21 Different Families, Including Families From Lybia and Iraq.	Bakri FG	Frontiers in immunology	2021	PMID: 33746979
Clinical and molecular findings of chronic granulomatous disease in Oman: family studies.	Al-Zadjali S	Clinical genetics	2015	PMID: 24446915
Prenatal diagnosis in two families with autosomal, p47(phox)-deficient chronic granulomatous disease due to a novel point mutation in NCF1.	de Boer M	Prenatal diagnosis	2002	PMID: 11920901

Text-mined citations for rs145360423 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000265.7(NCF1):c.579G>A (p.Trp193Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs145360423 ...