NM_000433.4(NCF2):c.230G>A (p.Arg77Gln) AND Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Mar 26, 2024
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:: RCV000002335.11

Allele description [Variation Report for NM_000433.4(NCF2):c.230G>A (p.Arg77Gln)]

NM_000433.4(NCF2):c.230G>A (p.Arg77Gln)

Gene:

NCF2:neutrophil cytosolic factor 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q25.3

Genomic location:

Preferred name:

NM_000433.4(NCF2):c.230G>A (p.Arg77Gln)

HGVS:

NC_000001.11:g.183586922C>T
NG_007267.1:g.8660G>A
NM_000433.4:c.230G>AMANE SELECT
NM_001127651.3:c.230G>A
NM_001190789.2:c.230G>A
NM_001190794.2:c.230G>A
NP_000424.2:p.Arg77Gln
NP_000424.2:p.Arg77Gln
NP_001121123.1:p.Arg77Gln
NP_001177718.1:p.Arg77Gln
NP_001177723.1:p.Arg77Gln
LRG_88t1:c.230G>A
LRG_88:g.8660G>A
LRG_88p1:p.Arg77Gln
NC_000001.10:g.183556057C>T
NM_000433.3:c.230G>A
NM_000433.4:c.230G>A
P19878:p.Arg77Gln

Protein change:

R77Q; ARG77GLN

Links:

UniProtKB: P19878#VAR_017388; UniProtKB/Swiss-Prot: VAR_017388; OMIM: 608515.0008; dbSNP: rs119103275

NCBI 1000 Genomes Browser:

rs119103275

Molecular consequence:

NM_000433.4:c.230G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127651.3:c.230G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001190789.2:c.230G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001190794.2:c.230G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2
Synonyms:: CGD, AUTOSOMAL RECESSIVE CYTOCHROME b-POSITIVE, TYPE II; GRANULOMATOUS DISEASE, CHRONIC, DUE TO NCF2 DEFICIENCY; GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL RECESSIVE, 2
Identifiers:: MONDO: MONDO:0009310; MedGen: C1856245; Orphanet: 379; OMIM: 233710

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000022493	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 1999)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000090882	UniProtKB/Swiss-Prot	no classification provided	not provided	germline	not provided	PubMed (1) [See all records that cite this PMID]
SCV001386227	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 27, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10598813, 20167518, 28492532
SCV004807433	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 26, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	1	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Autosomal recessive chronic granulomatous disease caused by novel mutations in NCF-2, the gene encoding the p67-phox component of phagocyte NADPH oxidase.

Noack D, Rae J, Cross AR, Muñoz J, Salmen S, Mendoza JA, Rossi N, Curnutte JT, Heyworth PG.

Hum Genet. 1999 Nov;105(5):460-7.

PubMed [citation]

PMID:: 10598813

Hematologically important mutations: the autosomal recessive forms of chronic granulomatous disease (second update).

Roos D, Kuhns DB, Maddalena A, Bustamante J, Kannengiesser C, de Boer M, van Leeuwen K, Köker MY, Wolach B, Roesler J, Malech HL, Holland SM, Gallin JI, Stasia MJ.

Blood Cells Mol Dis. 2010 Apr 15;44(4):291-9. doi: 10.1016/j.bcmd.2010.01.009. Epub 2010 Feb 18. Review.

PubMed [citation]

PMID:: 20167518
PMCID:: PMC4568122

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000022493.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a family with p67-phox-deficient chronic granulomatous disease (CGD2; 233710), Noack et al. (1999) identified compound heterozygosity for 2 mutations in the NCF2 gene: a 230G-A transition, resulting in an arg77-to-gln (R77Q) substitution inherited from the mother, and a nonsense mutation, 298C-T, which changed codon 100 from CAG (gln) to TAG (stop) (Q100X; 608515.0009) in the allele inherited from the father.

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

From UniProtKB/Swiss-Prot, SCV000090882.1

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

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001386227.4

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

Description

This sequence change replaces arginine with glutamine at codon 77 of the NCF2 protein (p.Arg77Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs119103275, ExAC 0.001%). This missense change has been observed in individual(s) with chronic granulomatous disease (PMID: 10598813, 20167518). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2247). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004807433.1

#	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	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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