H6PD R453Q - GET-Evidence


H6PD R453Q

(H6PD Arg453Gln)

Short summary

This common variant may have a small pathogenic effect by contributing to cortisone reductase deficiency (a rare abnormality) when homozygous and combined with a serious pathogenic variant. The same authors have tested and ruled out a contribution to polycystic ovary syndrome (similar phenotype, more common disease).

Variant evidence
Computational -1

Polyphen 2 predicts benign effect, BLOSUM100 score indicates this is not a disruptive amino acid change

Functional 1

Reduced enzyme activity

See 12858176.

Case/Control 3

See 12858176.


Familial data did not do more than establish heterozygous parental genotypes for the two homozygous individuals.

Clinical importance
Severity 3
Treatability -
Penetrance 1

High allele frequency means that any pathogenic effect in this variant must be quite rare.

See unpublished research (below).



Low clinical importance, Uncertain pathogenic

(The "low clinical importance, uncertain" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern


Summary of published research, and additional commentary

Incidence of this disease is unclear but appears to be quite rare. Draper et al. 2003 describe it as “characterized by hirsutism, menstrual irregularity with anovulatory infertility, obesity, insulin resistance and hyperandrogenism”.

In contrast, this variant has a very high allele frequency. If this variant is associated with the disease, homozygotes must still have a very low chance of disease. An allele frequency of 40% means that 16% of the population is homozygous for this variant — if the disease has an incidence of less than 1 in 1000 people then not more than 0.6% of homozygotes could have the disease.

Allele frequency

  • A @ chr1:9323910: 30.9% (3323/10758) in EVS
  • A @ chr1:9246496: 35.9% (46/128) in GET-Evidence
  • Frequency shown in summary reports: 30.9% (3323/10758)


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PubMed PMID: 12858176

This variant was seen homozygously in two of three individuals studied with cortisone reductase deficiency; it was homozygous wildtype in the remaining individual. Case var/var: 2, case var/wt: 0, case wt/wt: 1. 100 Scottish controls: var/var: 3, var/wt: 34, wt/wt: 63. Also, 49 Indo-Asian controls: var/var: 2, var/wt: 17, wt/wt: 30.

Combined controls: var/var: 5, var/wt: 51, wt/wt: 93. Looking at allele frequencies, this has a p-value of p=0.02. A recessive hypothesis gives it p=0.005. The authors report p=0.0008.

The authors report that expressed mutant cDNA had less than 50% enzyme activity.

San Millán JL, Botella-Carretero JI, Alvarez-Blasco F, Luque-Ramírez M, Sancho J, Moghetti P, Escobar-Morreale HF. A study of the hexose-6-phosphate dehydrogenase gene R453Q and 11beta-hydroxysteroid dehydrogenase type 1 gene 83557insA polymorphisms in the polycystic ovary syndrome. J Clin Endocrinol Metab. 2005 Jul;90(7):4157-62. Epub 2005 Apr 12. PubMed PMID: 15827106.


Draper N, Powell BL, Franks S, Conway GS, Stewart PM, McCarthy MI. Variants implicated in cortisone reductase deficiency do not contribute to susceptibility to common forms of polycystic ovary syndrome. Clin Endocrinol (Oxf). 2006 Jul;65(1):64-70. PubMed PMID: 16817821.




hu034DB1 - CGI sample GS00253-DNA_A02_200_37
het A @ chr1:9323910


hu0D879F - CGI sample GS00253-DNA_G01_200_37
het A @ chr1:9323910














huAE6220 - CGI sample GS00253-DNA_H01_200_37
het A @ chr1:9323910



huC30901 - CGI sample GS00253-DNA_B01_200_37
het A @ chr1:9323910




GS07357 - var-GS07357-1100-36-ASM
hom A @ chr1:9246497


GS18501 - var-GS18501-1100-36-ASM
het A @ chr1:9246497


GS18502 - var-GS18502-1100-36-ASM
het A @ chr1:9246497


GS18504 - var-GS18504-1100-36-ASM
hom A @ chr1:9246497


GS18526 - var-GS18526-1100-36-ASM
het A @ chr1:9246497


GS18537 - var-GS18537-1100-36-ASM
hom A @ chr1:9246497


GS18555 - var-GS18555-1100-36-ASM
het A @ chr1:9246497


GS18558 - var-GS18558-1100-36-ASM
het A @ chr1:9246497


GS18940 - var-GS18940-1100-36-ASM
het A @ chr1:9246497


GS18942 - var-GS18942-1100-36-ASM
het A @ chr1:9246497


GS18947 - var-GS18947-1100-36-ASM
hom A @ chr1:9246497


GS19017 - var-GS19017-1100-36-ASM
het A @ chr1:9246497


GS19026 - var-GS19026-1100-36-ASM
het A @ chr1:9246497


GS19129 - var-GS19129-1100-36-ASM
hom A @ chr1:9246497


GS19238 - var-GS19238-1100-36-ASM
het A @ chr1:9246497


GS19239 - var-GS19239-1100-36-ASM
het A @ chr1:9246497


GS19240 - var-GS19240-1100-36-ASM
het A @ chr1:9246497


GS19649 - var-GS19649-1100-36-ASM
het A @ chr1:9246497


GS19669 - var-GS19669-1100-36-ASM
het A @ chr1:9246497


GS19700 - var-GS19700-1100-36-ASM
hom A @ chr1:9246497


GS19701 - var-GS19701-1100-36-ASM
het A @ chr1:9246497


GS19703 - var-GS19703-1100-36-ASM
hom A @ chr1:9246497


GS19704 - var-GS19704-1100-36-ASM
hom A @ chr1:9246497


GS19735 - var-GS19735-1100-36-ASM
het A @ chr1:9246497


GS20509 - var-GS20509-1100-36-ASM
het A @ chr1:9246497


Other external references

  • rs6688832
  • Score: 0.004 (benign)

Other in silico analyses

  • NBLOSUM100 score = 0
  • GET-Evidence autoscore = 4

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Gene search

"GENE" or "GENE A123C":

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