G6PD A- AND Glucose 6 phosphate dehydrogenase deficiency

Clinical significance:Pathogenic (Last evaluated: Mar 31, 2000)

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000011075.15

Alleles description [Variation Report for G6PD A-]

NM_000402.4(G6PD):c.466A>G (p.Asn156Asp)

Gene:
G6PD:glucose-6-phosphate dehydrogenase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Xq28
Genomic location:
Preferred name:
NM_000402.4(G6PD):c.466A>G (p.Asn156Asp)
Other names:
G6PD, ASN126ASP
HGVS:
  • NC_000023.11:g.154535277T>C
  • NG_009015.2:g.17296A>G
  • NM_000402.4:c.466A>G
  • NM_001042351.3:c.376A>G
  • NM_001360016.2:c.376A>GMANE SELECT
  • NP_000393.4:p.Asn156Asp
  • NP_001035810.1:p.Asn126Asp
  • NP_001035810.1:p.Asn126Asp
  • NP_001035810.1:p.Asn126Asp
  • NP_001346945.1:p.Asn126Asp
  • NC_000023.10:g.153763492T>C
  • NM_000402.3:c.466A>G
  • NM_001042351.1:c.376A>G
  • NM_001042351.2:c.376A>G
Protein change:
N126D; ASN126ASP
Links:
OMIM: 305900.0001; OMIM: 305900.0002; OMIM: 305900.0023; dbSNP: rs1050829
NCBI 1000 Genomes Browser:
rs1050829
Molecular consequence:
  • NM_000402.4:c.466A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042351.3:c.376A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001360016.2:c.376A>G - missense variant - [Sequence Ontology: SO:0001583]

NM_000402.4(G6PD):c.292G>A (p.Val98Met)

Gene:
G6PD:glucose-6-phosphate dehydrogenase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Xq28
Genomic location:
Preferred name:
NM_000402.4(G6PD):c.292G>A (p.Val98Met)
Other names:
G6PD, VAL68MET; G6PD BETICA; G6PD CASTILLA; G6PD DISTRITO FEDERAL; G6PD TEPIC
HGVS:
  • NC_000023.11:g.154536002C>T
  • NG_009015.2:g.16571G>A
  • NM_000402.4:c.292G>A
  • NM_001042351.3:c.202G>A
  • NM_001360016.2:c.202G>AMANE SELECT
  • NP_000393.4:p.Val98Met
  • NP_001035810.1:p.Val68Met
  • NP_001035810.1:p.Val68Met
  • NP_001035810.1:p.Val68Met
  • NP_001346945.1:p.Val68Met
  • NC_000023.10:g.153764217C>T
  • NG_009015.1:g.16571G>A
  • NM_000402.3:c.292G>A
  • NM_001042351.1:c.202G>A
  • NM_001042351.2:c.202G>A
Protein change:
V68M; VAL68MET
Links:
PharmGKB: 981352141; PharmGKB Clinical Annotation: 981352141; OMIM: 305900.0002; OMIM: 305900.0054; dbSNP: rs1050828
NCBI 1000 Genomes Browser:
rs1050828
Molecular consequence:
  • NM_000402.4:c.292G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042351.3:c.202G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001360016.2:c.202G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Glucose 6 phosphate dehydrogenase deficiency
Synonyms:
G6PD A-
Identifiers:
MONDO: MONDO:0005775; MedGen: C2939465

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000031301OMIMno assertion criteria providedPathogenic
(Mar 31, 2000)
germlineliterature only

PubMed (16)
[See all records that cite these PMIDs]

Beutler, E., Matsumoto, F. A new glucose 6-phosphate dehydrogenase variant: G6PD (-) Los Angeles. I.R.C.S. 5: 89, 1977.

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Details of each submission

From OMIM, SCV000031301.9

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (16)

Description

Babalola et al. (1976) predicted that the A- mutation may have occurred in an individual carrying the A+ mutation. A black individual with the G6PD A- phenotype but no mutation at nucleotide 202 suggested that this individual may have another mutation that caused instability and thus deficiency of the enzyme. Yoshida and Takizawa (1988) presented evidence that the A- gene evolved by stepwise mutations through the A+ gene.

Vulliamy et al. (1988) cloned and sequenced 7 mutant G6PD alleles. A single point mutation in the African variant G6PD A does not result in deficiency of the enzyme. The other 6 mutants, including G6PD A-, were all associated with enzyme deficiency. Two different point mutations were found in G6PD A-, 1 of which was the same as that in G6PD A. See Yoshida et al. (1967). Hirono and Beutler (1988) demonstrated a substitution of methionine for valine at position 68 resulting from a G-to-A change at nucleotide 202 (in exon 4). The in vivo instability of the enzyme is the result of this change. The gene also has the change at amino acid 126 characteristic of G6PD A. See Vulliamy et al. (1988).

Beutler et al. (1989) performed haplotyping with 4 polymorphic restriction sites in the G6PD locus in DNA samples from 29 males with the G6PD A- phenotype and 14 males with a G6PD B phenotype. All G6PD A- subjects with the G6PD A- (202A/376G) genotype, regardless of population origin, shared identical haplotypes. The 5 populations screened were black (16), Puerto Rican (2), Mexican (2), white US (1), and Spanish (3). One G6PD A- male was of the 376G/680T genotype and 2 were of the 376G/968C genotype. One of the restriction sites is uncommon in the populations studied; thus, Beutler and Kuhl (1990) considered it likely that the G6PD A- mutation at nucleotide 202 arose relatively recently and in a single person.

Calabro et al. (1990) found this mutation, regarded as characteristically African, in an unselected sample of 1,524 schoolboys of the province of Matera in Southern Italy.

Beutler et al. (1991) found that 3 previously reported electrophoretically fast Mexican G6PD variants--G6PD Distrito Federal (Lisker et al., 1981), G6PD Tepic (Lisker et al., 1985), and G6PD Castilla (Lisker et al., 1977)--all showed the changes characteristic of G6PD A- (202A/376G) and had the haplotype characteristic of G6PD A- in Africa. G6PD Betica (Vives-Corrons and Pujades, 1982; Vives-Corrons et al., 1980), which is frequent in Spain, also had the same characteristics. Since the PvuII+ genotype is rare in Europe, the G6PD Betica mutation was presumably imported from Africa.

Hirono and Beutler (1988) found 2 other mutations that produced the G6PD A- phenotype: arg227-to-leu and leu323-to-pro. In both cases the mutations existed on the G6PD A background, i.e., the asn126-to-asp substitution.

Town et al. (1992) demonstrated that both the val68-to-met and the asn126-to-asp mutations found in G6PD A- are necessary to produce the G6PD-deficient phenotype (rather than the val68-to-met mutation having happened to arise in an A+ gene in the first instance). They approached the question by introducing G6PD B, A, A-, and G6PD val68-to-met in a bacterial expression system and analyzing their biochemical properties. With each of the 2 mutations alone, they found a slight decrease in both the specific activity and the yield of enzyme protein when compared to G6PD B. When both mutations were introduced together, there was a roughly additive effect on specific activity, but a much more drastic effect on enzyme yield which was reduced to 4% of normal. They inferred that the coexistence of the 2 mutations acted synergistically in causing instability of the enzyme. This would explain why a B- phenotype has only very rarely been observed. (Comparable results were produced when the replacement gln119-to-glu was combined with val68 to met.)

G6PD A- is the most common polymorphic variant associated with deficiency of G6PD in African populations, accounting for 20 to 40% of the affected population in western and central Africa; the most common nondeficient polymorphic variant in Africa is G6PD A. The G6PD A- mutation at position 68 alone has not been detected in any variant; this, together with further haplotyping analyses, led Vulliamy et al. (1992) to suggest that the nondeficient single mutant G6PD A is more ancient than the deficient double mutant G6PD A-.

Gomez-Gallego et al. (2000) performed structural studies on the doubly mutant G6PD A-. The changes they observed did not affect the active site of the mutant protein, since its spatial position was unmodified. The result of the structural changes was a loss of folding determinants, leading to a protein with decreased intracellular stability. Gomez-Gallego et al. (2000) suggested that the resultant protein was the cause of the enzyme deficiency in the red blood cell, which is unable to perform de novo protein synthesis.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 16, 2021

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