NM_138387.4(G6PC3):c.130C>T (p.Pro44Ser) AND Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Oct 13, 2023
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:: RCV000192087.10

Allele description [Variation Report for NM_138387.4(G6PC3):c.130C>T (p.Pro44Ser)]

NM_138387.4(G6PC3):c.130C>T (p.Pro44Ser)

Genes:

LOC130060959:ATAC-STARR-seq lymphoblastoid active region 12250 [Gene]
G6PC3:glucose-6-phosphatase catalytic subunit 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q21.31

Genomic location:

Preferred name:

NM_138387.4(G6PC3):c.130C>T (p.Pro44Ser)

Other names:

NP_612396.1:p.Phe44Ser

HGVS:

NC_000017.11:g.44071095C>T
NG_015818.1:g.5366C>T
NM_001319945.2:c.130C>T
NM_001384165.1:c.-275C>T
NM_001384166.1:c.-410C>T
NM_001384167.1:c.-400C>T
NM_001384168.1:c.-312+381C>T
NM_138387.4:c.130C>TMANE SELECT
NP_001306874.1:p.Pro44Ser
NP_612396.1:p.Pro44Ser
NP_612396.1:p.Pro44Ser
LRG_182t1:c.130C>T
LRG_182:g.5366C>T
LRG_182p1:p.Pro44Ser
NC_000017.10:g.42148463C>T
NM_138387.3:c.130C>T
Q9BUM1:p.Pro44Ser

Protein change:

P44S

Links:

UniProtKB: Q9BUM1#VAR_072753; dbSNP: rs775224457

NCBI 1000 Genomes Browser:

rs775224457

Molecular consequence:

NM_001384165.1:c.-275C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001384166.1:c.-410C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001384167.1:c.-400C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001384168.1:c.-312+381C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001319945.2:c.130C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_138387.4:c.130C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency
Synonyms:: Severe congenital neutropenia 4, autosomal recessive; PULMONARY ARTERIAL HYPERTENSION, LEUKOPENIA, AND ATRIAL SEPTAL DEFECT; Dursun syndrome
Identifiers:: MONDO: MONDO:0012930; MedGen: C2751630; Orphanet: 331176; OMIM: 612541

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000222643	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000594899	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 3, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004298219	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 13, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 21385794, 22469094, 27577878, 29163546, 22050868, 25492228, 31321910, 32623377, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000222643

GeneReviews

no classification provided

not provided

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV000594899

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 3, 2016)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004298219

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 13, 2023)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

G6PC3 mutations are associated with a major defect of glycosylation: a novel mechanism for neutrophil dysfunction.

Hayee B, Antonopoulos A, Murphy EJ, Rahman FZ, Sewell G, Smith BN, McCartney S, Furman M, Hall G, Bloom SL, Haslam SM, Morris HR, Boztug K, Klein C, Winchester B, Pick E, Linch DC, Gale RE, Smith AM, Dell A, Segal AW.

Glycobiology. 2011 Jul;21(7):914-24. doi: 10.1093/glycob/cwr023. Epub 2011 Mar 8.

PubMed [citation]

PMID:: 21385794
PMCID:: PMC3110488

See all PubMed Citations (10)

Details of each submission

From GeneReviews, SCV000222643.2

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

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

From Genetic Services Laboratory, University of Chicago, SCV000594899.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004298219.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 44 of the G6PC3 protein (p.Pro44Ser). This variant is present in population databases (rs775224457, gnomAD 0.03%). This missense change has been observed in individual(s) with G6PC3-related conditions (PMID: 21385794, 22469094, 27577878, 29163546). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 189781). 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. Experimental studies have shown that this missense change affects G6PC3 function (PMID: 25492228). This variant disrupts the p.Pro44 amino acid residue in G6PC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22050868, 25492228, 31321910, 32623377). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	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: Oct 20, 2024

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