ClinVar Genomic variation as it relates to human health
NM_138387.4(G6PC3):c.778G>C (p.Gly260Arg)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_138387.4(G6PC3):c.778G>C (p.Gly260Arg)
Variation ID: 30874 Accession: VCV000030874.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 44075780 (GRCh38) [ NCBI UCSC ] 17: 42153148 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 4, 2013 Feb 14, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_138387.4:c.778G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_612396.1:p.Gly260Arg missense NM_001319945.2:c.*71G>C 3 prime UTR NM_001384165.1:c.433G>C NP_001371094.1:p.Gly145Arg missense NM_001384166.1:c.433G>C NP_001371095.1:p.Gly145Arg missense NM_001384167.1:c.433G>C NP_001371096.1:p.Gly145Arg missense NM_001384168.1:c.433G>C NP_001371097.1:p.Gly145Arg missense NC_000017.11:g.44075780G>C NC_000017.10:g.42153148G>C NG_015818.1:g.10051G>C LRG_182:g.10051G>C LRG_182t1:c.778G>C LRG_182p1:p.Gly260Arg Q9BUM1:p.Gly260Arg - Protein change
- G260R, G145R
- Other names
- G6PC3, GLY260ARG
- Canonical SPDI
- NC_000017.11:44075779:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00006
Exome Aggregation Consortium (ExAC) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
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 | ||
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HI score
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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. |
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G6PC3 | - | - |
GRCh38 GRCh37 |
321 | 399 |
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. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000023859.26 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 3, 2023 | RCV000986189.16 |
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. |
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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001135100.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(Oct 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV000807607.4
First in ClinVar: Oct 05, 2015 Last updated: Dec 24, 2023 |
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Pathogenic
(Sep 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002571647.2
First in ClinVar: Sep 17, 2022 Last updated: Mar 04, 2023 |
Comment:
Reported as a common pathogenic variant among individuals of European background (Banka and Newman, 2013); Published functional studies demonstrate a damaging effect with no detectable … (more)
Reported as a common pathogenic variant among individuals of European background (Banka and Newman, 2013); Published functional studies demonstrate a damaging effect with no detectable enzyme activity (Lin et al., 2015); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23441086, 19118303, 19775295, 20220065, 20616219, 23180359, 25491320, 23758768, 25492228) (less)
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Pathogenic
(Jan 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001716318.2
First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024 |
Comment:
PP1, PP3, PM3_very_strong, PS3_moderate, PS4
Number of individuals with the variant: 2
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Pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001218449.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 260 of the G6PC3 protein (p.Gly260Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 260 of the G6PC3 protein (p.Gly260Arg). This variant is present in population databases (rs200478425, gnomAD 0.01%). This missense change has been observed in individuals with syndromic severe congenital neutropenia (PMID: 19118303, 20616219, 23180359, 23441086). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30874). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt G6PC3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects G6PC3 function (PMID: 25492228). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 14, 2010)
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no assertion criteria provided
Method: literature only
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NEUTROPENIA, SEVERE CONGENITAL, 4, AUTOSOMAL RECESSIVE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000045150.2
First in ClinVar: Apr 04, 2013 Last updated: Nov 14, 2020 |
Comment on evidence:
In a German boy with severe congenital neutropenia-4 (SCN4; 612541), Boztug et al. (2009) identified a homozygous 778G-C transversion in the G6PC3 gene, resulting in … (more)
In a German boy with severe congenital neutropenia-4 (SCN4; 612541), Boztug et al. (2009) identified a homozygous 778G-C transversion in the G6PC3 gene, resulting in a gly260-to-arg (G260R) substitution. Other features included growth retardation, type 2 atrial septal defect, cryptorchidism with genital dysplasia, microcephaly, inner-ear hearing loss, prominent superficial venous pattern, and intermittent thrombocytopenia. McDermott et al. (2010) identified homozygosity for the G260R substitution in 2 sibs with SCN4 and multiple clinical abnormalities. The patients had a favorable response to G-CSF treatment, which resulted in increased peripheral neutrophil counts. The G260R mutation occurred in a conserved residue in the seventh transmembrane domain and caused a complete loss of enzyme activity. Bone marrow biopsies of both patients showed the presence of mature neutrophils despite markedly decreased neutrophils in the peripheral blood. The bone marrow also showed a predominance of atypical mononuclear megakaryocytes, myeloid hyperplasia, and vacuolization of the myeloid precursors. These features were consistent with myelokathexis and cytokine activation. Peripheral blood neutrophils and NK cells had increased expression of CXCR4 (162643), and G-CSF treatment resulted in a dose-dependent decrease of CXCR4. McDermott et al. (2010) concluded that the neutropenia in their patients resulted from a combination of decreased release of mature neutrophils from the bone marrow, increased apoptosis of peripheral blood neutrophils, and decreased superoxide production. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000222646.2
First in ClinVar: Oct 05, 2015 Last updated: Oct 01, 2022 |
Ethnicity/Population group: European
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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G6PC3 Deficiency. | Adam MP | - | 2015 | PMID: 25879134 |
Functional analysis of mutations in a severe congenital neutropenia syndrome caused by glucose-6-phosphatase-β deficiency. | Lin SR | Molecular genetics and metabolism | 2015 | PMID: 25492228 |
Clinical spectrum and long-term follow-up of 14 cases with G6PC3 mutations from the French Severe Congenital Neutropenia Registry. | Desplantes C | Orphanet journal of rare diseases | 2014 | PMID: 25491320 |
A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations. | Banka S | Orphanet journal of rare diseases | 2013 | PMID: 23758768 |
A novel phenotype variant of severe congenital neutropenia caused by G6PC3 deficiency. | Estévez OA | Pediatric blood & cancer | 2013 | PMID: 23441086 |
Inflammatory bowel disease and T cell lymphopenia in G6PC3 deficiency. | Bégin P | Journal of clinical immunology | 2013 | PMID: 23180359 |
Severe congenital neutropenia resulting from G6PC3 deficiency with increased neutrophil CXCR4 expression and myelokathexis. | McDermott DH | Blood | 2010 | PMID: 20616219 |
Digenic mutations in severe congenital neutropenia. | Germeshausen M | Haematologica | 2010 | PMID: 20220065 |
Prevalence of mutations in ELANE, GFI1, HAX1, SBDS, WAS and G6PC3 in patients with severe congenital neutropenia. | Xia J | British journal of haematology | 2009 | PMID: 19775295 |
A syndrome with congenital neutropenia and mutations in G6PC3. | Boztug K | The New England journal of medicine | 2009 | PMID: 19118303 |
Text-mined citations for rs200478425 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.