NM_000175.5(GPI):c.1040G>A (p.Arg347His) AND Hemolytic anemia due to glucophosphate isomerase deficiency

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Sep 21, 2022
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:: RCV000014610.40

Allele description [Variation Report for NM_000175.5(GPI):c.1040G>A (p.Arg347His)]

NM_000175.5(GPI):c.1040G>A (p.Arg347His)

Gene:

GPI:glucose-6-phosphate isomerase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.11

Genomic location:

Preferred name:

NM_000175.5(GPI):c.1040G>A (p.Arg347His)

Other names:

R346H

HGVS:

NC_000019.10:g.34394044G>A
NG_012838.3:g.39453G>A
NM_000175.5:c.1040G>AMANE SELECT
NM_001184722.1:c.1073G>A
NM_001289789.1:c.1157G>A
NM_001289790.3:c.956G>A
NM_001329909.1:c.1040G>A
NM_001329910.1:c.1040G>A
NM_001329911.2:c.1040G>A
NP_000166.2:p.Arg347His
NP_001171651.1:p.Arg358His
NP_001276718.1:p.Arg386His
NP_001276719.1:p.Arg319His
NP_001316838.1:p.Arg347His
NP_001316839.1:p.Arg347His
NP_001316840.1:p.Arg347His
LRG_1178t1:c.1040G>A
LRG_1178:g.39453G>A
LRG_1178p1:p.Arg347His
NC_000019.9:g.34884949G>A
NM_000175.4:c.[1040G>A]
P06744:p.Arg347His

Protein change:

R319H; ARG346HIS

Links:

UniProtKB: P06744#VAR_002530; OMIM: 172400.0002; dbSNP: rs137853583

NCBI 1000 Genomes Browser:

rs137853583

Molecular consequence:

NM_000175.5:c.1040G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001184722.1:c.1073G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001289789.1:c.1157G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001289790.3:c.956G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001329909.1:c.1040G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001329910.1:c.1040G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001329911.2:c.1040G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hemolytic anemia due to glucophosphate isomerase deficiency
Synonyms:: Hemolytic anemia, nonspherocytic, due to glucose phosphate isomerase deficiency
Identifiers:: MONDO: MONDO:0013275; MedGen: C3150730; Orphanet: 712; OMIM: 613470

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000034865	OMIM	no assertion criteria provided	Pathogenic (Mar 1, 1993)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001157742	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Jul 28, 2018)	germline	clinical testing	Citation Link,
SCV002073109	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003824719	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 21, 2022)	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	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
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

DNA sequence abnormalities in human glucose 6-phosphate isomerase deficiency.

Walker JI, Layton DM, Bellingham AJ, Morgan MJ, Faik P.

Hum Mol Genet. 1993 Mar;2(3):327-9. No abstract available.

PubMed [citation]

PMID:: 8499925

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

Details of each submission

From OMIM, SCV000034865.2

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

Description

For discussion of the arg346-to-his (R346H) mutation in the GPI gene that was found in compound heterozygous state in a patient with chronic nonspherocytic hemolytic anemia associated with severe deficiency of red cell glucose phosphate isomerase (613470) by Walker et al. (1993), see 172400.0001.

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001157742.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	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 Neuberg Centre For Genomic Medicine, NCGM, SCV002073109.2

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

Description

The missense variant c.1040G>A (p.Arg347His) in the GPI gene has been reported previously in compound heterozygous and homozygous state in individuals affected with Hereditary Non-Spherocytic Hemolytic Anemia. Functional studies show that the residue is involved in enzyme dimerization and Arg347His leads to the loss of hydrogen bonds on the neighbouring chains of dimers, probably losing dimerization activity (Jamwal et al., 2017; Kedar et al., 2019). This variant is reported with the allele frequency (0.001%) in the gnomAD and novel (not in any individuals) in the 1000 genome database. It is submitted to ClinVar as Pathogenic. The amino acid Arginine at position 347 is changed to a Histidine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Arg347His in GPI is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

#	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 Revvity Omics, Revvity, SCV003824719.2

#	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: Apr 6, 2024

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