NM_000402.4(G6PD):c.292G>A (p.Val98Met) AND Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Germline classification:: Pathogenic/Likely pathogenic (18 submissions)
Last evaluated:: Apr 4, 2024
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:: RCV000079404.37

Allele description [Variation Report for NM_000402.4(G6PD):c.292G>A (p.Val98Met)]

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; G6PD Asahi

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_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
NM_001042351.3:c.202G>A
NM_001360016.2:c.202G>A

Protein change:

V68M; VAL68MET

Links:

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]

Observations:

Condition(s)

Name:: Anemia, nonspherocytic hemolytic, due to G6PD deficiency
Synonyms:: Hemolytic anemia due to G6PD deficiency; Favism, susceptibility to; Class I glucose-6-phosphate dehydrogenase deficiency
Identifiers:: MONDO: MONDO:0010480; MedGen: C2720289; Orphanet: 466026; OMIM: 300908

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000238425	Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq	no assertion criteria provided	Pathogenic (Feb 20, 2015)	germline	research	PubMed (5) [See all records that cite these PMIDs] 1303173, 23144702, 3393536, 21153663, 21931771
SCV000494242	Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 28, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000647800	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 20, 2018)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 2836867, 3393536, 1303173, 4359638, 2572288, 6015571, 16356170, 24505519, 10734064, 23006493, 11852882, 28492532
SCV000677948	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Pathogenic (Oct 15, 2015)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 1303173, 11852882, 7959686 Citation Link,
SCV000711717	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 26, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 25201310, 11852882, 23144702, 27040960, 21479984, 28512736, 2836867, 25741868
SCV000891509	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	no assertion criteria provided	Pathogenic (Dec 30, 2017)	unknown	curation
SCV001132889	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	no assertion criteria provided	Pathogenic (Aug 25, 2019)	germline	clinical testing
SCV001142114	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001482573	Baylor Genetics - CSER-TexasKidsCanSeq	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 26, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001749894	GenomeConnect - Invitae Patient Insights Network	no classification provided	not provided	unknown	phenotyping only
SCV002059871	Centogene AG - the Rare Disease Company	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 2, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002072536	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 12, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002599322	Dunham Lab, University of Washington	criteria provided, single submitter (Bayesian ACMG Guidelines, 2018)	Pathogenic (Aug 12, 2022)	maternal	curation	PubMed (9) [See all records that cite these PMIDs] 28756180, 23006493, 11852882, 33636823, 32387609, 17018380, 34620237, 30045279, 29300386
SCV003806742	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 2, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003927912	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	no assertion criteria provided	Pathogenic (Apr 1, 2023)	germline	clinical testing
SCV004099377	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	no assertion criteria provided	Pathogenic (Oct 30, 2023)	germline	clinical testing
SCV004239032	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 8, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 10734064, 11852882, 1303173, 23006493, 25201310, 33636823, 3393536, 36150187, 25741868
SCV004809841	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 4, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	2	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	maternal	yes	not provided	not provided	not provided	not provided	not provided	curation
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, phenotyping only

Citations

PubMed

Genetic association analysis highlights new loci that modulate hematological trait variation in Caucasians and African Americans.

Lo KS, Wilson JG, Lange LA, Folsom AR, Galarneau G, Ganesh SK, Grant SF, Keating BJ, McCarroll SA, Mohler ER 3rd, O'Donnell CJ, Palmas W, Tang W, Tracy RP, Reiner AP, Lettre G.

Hum Genet. 2011 Mar;129(3):307-17. doi: 10.1007/s00439-010-0925-1. Epub 2010 Dec 12.

PubMed [citation]

PMID:: 21153663
PMCID:: PMC3442357

Path to facilitate the prediction of functional amino acid substitutions in red blood cell disorders--a computational approach.

B R, C GP.

PLoS One. 2011;6(9):e24607. doi: 10.1371/journal.pone.0024607. Epub 2011 Sep 13.

PubMed [citation]

PMID:: 21931771
PMCID:: PMC3172254

See all PubMed Citations (29)

Details of each submission

From Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq, SCV000238425.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (5)

Description

This heterozygous variant (c.202G>A; p.Val68Met) has been reported under the name of “Asahi variant” when no other variants are present on the same haplotype; the enzymatic activity was reduced to 41% of wild type. This variant have been previously published as part of the same haplotype (A- variant) which results in reduced enzymatic activity to 10-23% of normal activity.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen, SCV000494242.1

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

Description

The c.202G>A (p.Val68Met) missense variant is recognized as a disease-causing variant in the G6PD gene. Functional studies demonstrate reduced enzymatic activity of the G allele compared to WT. The prevalence of the variant in affected individuals (homozygous) is increased compared with the prevalence in controls and there is familial co-segregation with disease (Bwayo et al. 2013; Manjurano et al. 2012; Maiga et al. 2014; Shah et al. 2014; Pisani et al. 2012; Vulliamy et al. 1988; Odievre et al. 2011). Although the frequency of this variant in the African population within ExAC (http://exac.broadinstitute.org) is high it is consistent with observed and expected based on disease incidence (11.34%). Computational algorithms predict the variant has a damaging or deleterious effect. This variant is has been classified as pathogenic by multiple reputable clinical testing laboratories (Emory, Division of Human Genetics at Childrenâ€™s Hospital of Philadelphia). In summary, this variant c.202G>A (p.Val68Met) meets our criteria for a Pathogenic classification. We have confirmed this finding in our laboratory using Sanger sequencing.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000647800.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This sequence change replaces valine with methionine at codon 68 of the G6PD protein (p.Val68Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs1050828, ExAC 11%). ClinVar contains an entry for this variant (Variation ID: 37123).Â¬â€ This variant is also known as the Asashi variant or p.Val98Met in the literature. This variant frequently co-occurs with the c.376A>G (p.Asn126Asp) variant (rs1050829) in cis (on the same chromosome), which is known as the G6PD A- haplotype c.[202G>A; 376A>G] . The G6PD A- haplotype is the most prevalent G6PD deficiency variant in African populations which is present at 0.2% (PMID: 1303173, 24505519, 2572288, 4359638). ClinVar contains an entry for the G6PD A- haplotype (Variation ID: 10361). This variant has been reported to co-occur with another G6PD variant independent of the A- haplotype in a Japanese family affected with G6PD deficiency (PMID: 11852882). It has also been identified as homozygous independent of the A- haplotype in individuals suspected with G6PD deficiency (PMID: 23006493). While this variant alone has been shown to only mildly affect enzyme activity, the c.[202G>A; 376A>G] changes of the G6PD A- haplotype have been reported to act synergistically to cause dramatic reduction of the stability and enzymatic activity of the G6PD protein (PMID: 3393536, 1303173, 10734064, 6015571, 2836867, 16356170). For these reasons, this variant on the c.[202G>A; 376A>G] haplotype has been classified as 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

From Counsyl, SCV000677948.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000711717.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The p.Val98Met variant in G6PD (frequently reported as p.Val68Met on transcript NM_001042351.1) is a well-established pathogenic variant for glucose-6-phosphate dehydrogenase deficiency (G6PD) and has been shown to alter G6PD enzyme activity (Pal 2017 PMID: 28512736, Hirono 2002 PMID: 11852882, Hirono 1988 PMID: 2836867, Shah 2014 PMID: 25201310, Odièvre 2011 PMID: 21479984). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 37123) and has been identified in 11.6% (3560/30745) of African chromosomes, including 155 female homozygotes and 995 male hemizygotes, by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). The variant's high frequency is consistent with the prevalence of G6PD deficiency in African populations and is thought to be a result of a partial protection against malaria (Manjurano 2012 PMID: 23144702, Luzzatto 2016 PMID: 27040960). Computational prediction tools and conservation analysis are consistent with pathogenicity. Of note, this variant frequently co-occurs with the p.Asn156Asp in cis and is known as the G6PD A-allele, which is a class III variant with a moderate level of deficiency (10-60% activity). In summary, this variant meets criteria to be classified as pathogenic for X-linked G6PD deficiency. ACMG/AMP Criteria applied: PS4_VeryStrong, PS3_Moderate, PP3.

#	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 Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University, SCV000891509.2

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

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

From Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City, SCV001132889.1

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

From Mendelics, SCV001142114.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics - CSER-TexasKidsCanSeq, SCV001482573.2

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GenomeConnect - Invitae Patient Insights Network, SCV001749894.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	phenotyping only	not provided

Description

Variant interpreted as Uncertain significance and reported on 10-30-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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

From Centogene AG - the Rare Disease Company, SCV002059871.1

#	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 Institute of Human Genetics, University of Leipzig Medical Center, SCV002072536.1

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

Description

This variant was identifiedas hemizygous and togehter with NM_001042351.3:c.376A>G._x000D_ Criteria applied: PS4, PS3_SUP, PP3

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

From Dunham Lab, University of Washington, SCV002599322.1

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

Description

Variant found in three unrelated families, where hemizygotes present with deficiency, some with hyperbilirubinemia, jaundice, and anemia (PS4_M, PP4). Two son-and-mother pairs both have variant and decreased activity, and sons have additional symptoms (PP1). Decreased activity in red blood cells (3-71%) and when expressed in E. coli (PS3). Predicted to be damaging by SIFT and probably damaging by PolyPhen (PP3). Reported as pathogenic by multiple clinical testing groups (PP5). Post_P 0.994 (odds of pathogenicity 1516, Prior_P 0.1).

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

From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV003806742.1

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

Description

ACMG classification criteria: PS3 supporting, PS4 strong, PP3 supporting

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

From Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), SCV003927912.1

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

From Zotz-Klimas Genetics Lab, MVZ Zotz Klimas, SCV004099377.1

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

From Johns Hopkins Genomics, Johns Hopkins University, SCV004239032.1

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

Description

While G6PD c.202G>A in isolation (called Asahi variant) has occasionally been identified in individuals with G6PD deficiency, it has more commonly been reported to co-occur on the same haplotype with another variant c.376A>G; p.Asn126Asp (complex variant c.376A>G/c.202G>A is called A- variant) and this complex variant has also been observed in individuals with G6PD deficiency. However, G6PD c.376A>G in isolation is considered a non-deficient variant that does not cause disease, and has instead been shown to act as a genetic modifier, increasing the risk of G6PD deficiency by two-fold in individuals heterozygous for c.202G>A3. Functional studies support that the A- variant results in clinically significant G6PD enzyme deficiency. c.202G>A (rs1050828) is present in a large population dataset (gnomAD v2.1.1: 2365/205030 total alleles; 1.2%; 641 hemizygotes and 90 homozygotes), and has been reported in ClinVar (Variation ID 37123). We consider c.202G>A in G6PD to be 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

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004809841.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 20, 2024

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