VCV000001037.22 - ClinVar

NM_138387.4(G6PC3):c.758G>A (p.Arg253His)

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.

(5)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_138387.4(G6PC3):c.758G>A (p.Arg253His)

Variation ID: 1037 Accession: VCV000001037.22

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q21.31 17: 44075760 (GRCh38) [ NCBI UCSC ] 17: 42153128 (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 4, 2013	Oct 20, 2024	Dec 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_138387.4:c.758G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_612396.1:p.Arg253His	missense
NM_001319945.2:c.*51G>A		3 prime UTR
NM_001384165.1:c.413G>A	NP_001371094.1:p.Arg138His	missense
NM_001384166.1:c.413G>A	NP_001371095.1:p.Arg138His	missense
NM_001384167.1:c.413G>A	NP_001371096.1:p.Arg138His	missense
NM_001384168.1:c.413G>A	NP_001371097.1:p.Arg138His	missense
NC_000017.11:g.44075760G>A
NC_000017.10:g.42153128G>A
NG_015818.1:g.10031G>A
LRG_182:g.10031G>A
LRG_182t1:c.758G>A	LRG_182p1:p.Arg253His
	Q9BUM1:p.Arg253His

... more HGVS ... less HGVS

Protein change

R253H, R138H

Other names

G6PC3, ARG253HIS

Canonical SPDI

NC_000017.11:44075759: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.

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

ClinGen: CA339863 UniProtKB: Q9BUM1#VAR_055157 OMIM: 611045.0001 dbSNP: rs118203968 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.
G6PC3		-	-	GRCh38 GRCh37	324	404

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.
Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency	Pathogenic (3)	criteria provided, single submitter	Nov 1, 2023	RCV000001092.18
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 1, 2023	RCV003311633.18

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 (Nov 01, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002230550.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 19118303‚ 20717171‚ 21385794 Comment: This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 253 of the G6PC3 protein (p.Arg253His). … (more) This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 253 of the G6PC3 protein (p.Arg253His). This variant is present in population databases (rs118203968, gnomAD 0.002%). This missense change has been observed in individuals with severe congenital neutropenia (PMID: 19118303, 20717171, 21385794). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1037). 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: 19118303). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Aug 14, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005325206.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024	Comment: Published functional studies demonstrate a damaging effect on G6PC3 phosphatase activity (Boztug et al., 2009; Lin et al., 2015); In silico analysis supports that this … (more) Published functional studies demonstrate a damaging effect on G6PC3 phosphatase activity (Boztug et al., 2009; Lin et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21385794, 23196894, 27051561, 34964150, 20616219, 32051561, 19118303, 25491320, 20717171, 34305938, 25284454, 33259599, 25492228) (less)
Pathogenic (Dec 01, 2023)	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: SCV004009805.12 First in ClinVar: Jul 16, 2023 Last updated: Oct 20, 2024	Comment: G6PC3: PM3:Very Strong, PM2, PP1, PS3:Supporting Number of individuals with the variant: 3
Pathogenic (Jan 01, 2011)	no assertion criteria provided Method: literature only	NEUTROPENIA, SEVERE CONGENITAL, 4, AUTOSOMAL RECESSIVE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000021242.2 First in ClinVar: Apr 04, 2013 Last updated: Nov 14, 2020	Publications: PubMed (2) PubMed: 19118303‚ 20717171 Comment on evidence: In affected members of a large consanguineous kindred from Turkey with severe congenital neutropenia (SCN4; 612541), Boztug et al. (2009) identified a homozygous 758G-A transition … (more) In affected members of a large consanguineous kindred from Turkey with severe congenital neutropenia (SCN4; 612541), Boztug et al. (2009) identified a homozygous 758G-A transition in exon 6 of the G6PC3 gene, resulting in an arg253-to-his (R253H) substitution in a highly conserved residue. The mutation was not identified in 192 controls. The patients had neonatal sepsis, intermittent thrombocytopenia, cardiac defects, and prominent superficial venous pattern. Bone marrow smears showed decreased mature neutrophils. Both peripheral neutrophils and skin fibroblasts from the patients showed an increased susceptibility to apoptosis, but the neutrophils showed normal oxidative burst. In vitro functional expression studies showed that the mutant R253H protein had no phosphatase activity. Electron microscopic studies showed an enlarged rough endoplasmic reticulum, consistent with increased stress. In a large consanguineous kindred of Arab-Muslim descent in which 4 individuals had SCN4, Banka et al. (2011) identified a homozygous R253H mutation. (less)
not provided (-)	no classification provided Method: literature only	Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000222645.2 First in ClinVar: Oct 05, 2015 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 20717171 BookShelf: NBK285321 BookShelf: NBK285321 Ethnicity/Population group: Middle East

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 253 of the G6PC3 protein (p.Arg253His). This variant is present in population databases (rs118203968, gnomAD 0.002%). This missense change has been observed in individuals with severe congenital neutropenia (PMID: 19118303, 20717171, 21385794). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1037). 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: 19118303). For these reasons, this variant has been classified as Pathogenic.

Comment:

Published functional studies demonstrate a damaging effect on G6PC3 phosphatase activity (Boztug et al., 2009; Lin et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21385794, 23196894, 27051561, 34964150, 20616219, 32051561, 19118303, 25491320, 20717171, 34305938, 25284454, 33259599, 25492228)

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
G6PC3 Deficiency.	Adam MP	-	2015	PMID: 25879134
G6PC3 mutations are associated with a major defect of glycosylation: a novel mechanism for neutrophil dysfunction.	Hayee B	Glycobiology	2011	PMID: 21385794
Further delineation of the phenotype of severe congenital neutropenia type 4 due to mutations in G6PC3.	Banka S	European journal of human genetics : EJHG	2011	PMID: 20717171
A syndrome with congenital neutropenia and mutations in G6PC3.	Boztug K	The New England journal of medicine	2009	PMID: 19118303

Text-mined citations for rs118203968 ...

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 03, 2024

ClinVar Genomic variation as it relates to human health

NM_138387.4(G6PC3):c.758G>A (p.Arg253His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs118203968 ...