NM_000402.4(G6PD):c.1039G>A (p.Glu347Lys) AND Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Germline classification:: Pathogenic/Likely pathogenic (11 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:: RCV000800624.28

Allele description [Variation Report for NM_000402.4(G6PD):c.1039G>A (p.Glu347Lys)]

NM_000402.4(G6PD):c.1039G>A (p.Glu347Lys)

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.1039G>A (p.Glu347Lys)

Other names:

G6PD, GLU317LYS; G6PD Jamnaga; G6PD Kalyan; G6PD Kerala; G6PD Kerala-Kalyan; G6PD Rohini; p.Glu317Lys

HGVS:

NC_000023.11:g.154533044C>T
NG_009015.2:g.19529G>A
NM_000402.4:c.1039G>A
NM_001042351.3:c.949G>A
NM_001360016.2:c.949G>AMANE SELECT
NP_000393.4:p.Glu347Lys
NP_001035810.1:p.Glu317Lys
NP_001346945.1:p.Glu317Lys
NC_000023.10:g.153761259C>T
NM_000402.3:c.1039G>A
NM_001042351.1:c.949G>A
NM_001042351.2:c.949G>A
NM_001042351.3:c.949G>A
NM_001360016.2:c.949G>A

Protein change:

E317K; GLU317LYS

Links:

OMIM: 305900.0042; dbSNP: rs137852339

NCBI 1000 Genomes Browser:

rs137852339

Molecular consequence:

NM_000402.4:c.1039G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042351.3:c.949G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001360016.2:c.949G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Anemia, nonspherocytic hemolytic, due to G6PD deficiency (CNSHA1)
Synonyms:: Hemolytic anemia due to G6PD deficiency; Favism, susceptibility to; Class I glucose-6-phosphate dehydrogenase deficiency; See all synonyms [MedGen]
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
SCV000940353	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 17, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 1303182, 16528451, 15315792, 30097005, 27880809, 27535533, 22293322, 28492532
SCV001142106	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (May 27, 2022)	unknown	clinical testing	Citation Link,
SCV001443093	Lifecell International Pvt. Ltd	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002599307	Dunham Lab, University of Washington	criteria provided, single submitter (Bayesian ACMG Guidelines, 2018)	Pathogenic (Aug 12, 2022)	inherited	curation	PubMed (7) [See all records that cite these PMIDs] 18046504, 15315792, 27880809, 6714978, 5673160, 1303182, 29300386
SCV003921943	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 16, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22293322, 30097005, 31833391, 25741868
SCV003927899	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	no assertion criteria provided	Likely pathogenic (Apr 1, 2023)	germline	clinical testing
SCV003930288	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004040662	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 30, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004048378	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]
SCV004176186	New York Genome Center	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Pathogenic (May 3, 2023)	inherited	clinical testing	PubMed (8) [See all records that cite these PMIDs] 15996881, 1303182, 30097005, 16528451, 15315792, 27880809, 27535533, 33069889 Citation Link,
SCV004810370	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	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	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	curation
not provided	inherited	unknown	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Glucose-6-phosphate dehydrogenase mutations in Mon and Burmese of southern Myanmar.

Nuchprayoon I, Louicharoen C, Charoenvej W.

J Hum Genet. 2008;53(1):48-54. doi: 10.1007/s10038-007-0217-3. Epub 2007 Nov 28.

PubMed [citation]

PMID:: 18046504

See all PubMed Citations (16)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000940353.6

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

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 317 of the G6PD protein (p.Glu317Lys). This variant is present in population databases (rs137852339, gnomAD 1.1%), and has an allele count higher than expected for a pathogenic variant. This variant is a prevalent G6PD variant in the South Asian population, typically associated with partial reduction of enzyme activity (PMID: 1303182, 30097005, 16528451, 15315792, 30097005, 27880809, 27535533). By WHO classification, this is a Class III variant associated with moderate G6PD deficiency (10-60% enzyme activity) and hemolysis with stressors only (PMID: 22293322). This variant is also known as G6PD Kerala, G6PD Kalyan, G6PD Kerala‚ÄìKalyan, G6PD Jamnaga, and G6PD Rohini. ClinVar contains an entry for this variant (Variation ID: 10401). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on G6PD protein function. 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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV001142106.2

#	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 Lifecell International Pvt. Ltd, SCV001443093.1

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

Description

This variant in exon 9 of the G6PD gene results in the amino acid substitution from glutamic acid to lysine at codon 347 (p.Glu347Lys) with the sequence change of c.1039G>A (NM_000402.4). This variant was observed in a proband with a decreased level of G6PD enzyme (3.1 U/dl) which was screened for advanced newborn screening with confirmatory genetic reflex testing at Lifecell diagnostics. There is a small physicochemical difference between glutamic acid and lysine. The observed variant is not present in both the 1000 Genomes and gnomAD databases. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT are damaging. This is a Class III variant associated with moderate G6PD deficiency (10-60% enzyme activity) and hemolysis with stressors only. According to the previous studies this variant is also known as G6PD Kerala, G6PD Kalyan, G6PD Kerala Kalyan, G6PD Jamnaga, and G6PD Rohini. This variant has previously been reported for Glucose-6- phosphate dehydrogenase (G6PD) deficiency by Islam MT et al., 2018. The Missense Variants Z-Score for this variant is 2.60. Missense Variants Z-Score is produced by the Exome Aggregation Consortium (60,706 adult humans) by computing a signed Z score for the deviation of observed counts from the expected number. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer missense variants than expected. This variant is a prevalent G6PD variant in the South Asian population, typically associated with partial reduction of enzyme activity (Ahluwalia A et al. 1992; PMID: 1303182), (Islam MT et al. 2018; PMID: 30097005), ( Ninokata A et al, 2006; PMID: 16528451), ( Sukumar S et al. 2004; PMID: 15315792), ( Sarker SK et al. 2016; PMID: 27880809), (Minucci A et al, 2012; PMID: 22293322).

#	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 Dunham Lab, University of Washington, SCV002599307.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (7)

Description

Variant found in unrelated hemizygotes with G6PD deficiency but no other symptoms (PS4_M, PP4). Also segregates with deficiency in multiple brothers, and heterozygous sister has slightly decreased activity (PP1). Decreased activity in red blood cells of hemizygotes (19-52%) (PS3). Modeling predicts disruption of function (PP3). Reported as pathogenic by multiple clinical testing groups (PP5). Post_P 0.994 (odds of pathogenicity 1517, Prior_P 0.1).

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV003921943.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with G6PD deficient haemolytic anemia (favism) (MIM#300908). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - Variant is heterozygous. (I) 0305 - Variant is present in gnomAD >=0.01 and <0.03 for a recessive condition (v2: 94 heterozygotes, 1 homozygote, 132 hemizygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated G6PD C-terminal domain (DECIPHER). (I) 0705 - No comparable variants have previous evidence for pathogenicity. (I) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been classified as a G6PD Class III variant and is known as the Kerala-Kalyan variant. Individuals with this variant have moderate to mild G6PD enzyme activity (WHO recommendations; G6PD database; PMID: 22293322; 30097005, 31833391). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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 Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), SCV003927899.1

#	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 Intergen, Intergen Genetics and Rare Diseases Diagnosis Center, SCV003930288.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		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 Baylor Genetics, SCV004040662.1

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

From Neuberg Centre For Genomic Medicine, NCGM, SCV004048378.1

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

Description

The amino acid Glu at position 347 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. This variant is a prevalent G6PD variant in the South Asian population, typically associated with partial reduction of enzyme activity (Ahluwalia A et al, Islam MT et al). By WHO classification, this is a Class III variant associated with moderate G6PD deficiency (10-60% enzyme activity) and hemolysis with stressors only (Minucci A et al). This variant is also known as G6PD Kerala, G6PD Kalyan, G6PD Keralaâ€šÃ„Ã¬Kalyan, G6PD Jamnagar, and G6PD Rohini in the literature. The p.Glu347Lys variant in reported with the allele frequency of 0.1111% in gnomAD Exomes and is novel (not in any individuals) in1000 Genomes. This variant has been reported in Clinvar as Conflicting interpretations of pathogenicity - pathogenic/ uncertain significance. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Glu347Lys in G6PD 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 New York Genome Center, SCV004176186.1

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

Description

The hemizygous, maternally inherited c.949G>A p.(Glu317Lys) variant identified in the G6PD gene substitutes an evolutionarily conserved glutamic acid with Lysine at position 317/516 (exon 9/13) in the dimer interface region [PMID: 31294066] of the encoded protein. This variant is also called c.1039G>Ap.(Glu347Lys) based on transcript NM_000402.4, and is reported in ClinVar [ClinVar ID:10401] as Pathogenic. This variant is observed in 322 alleles (0.04% minor allele frequency with 6 homozygotes and 151 hemizygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us) including in 242 alleles(1.07% minor allele frequency with 1 homozygote and 148 hemizygotes) in South Asian subpopulation (gnomAD v2.1.1 and v3.1.2(non-Topmed)). In silico predictions are in favor of damaging effect for p.(Glu317Lys) (REVEL = 0.648). The p.(Glu317Lys) variant in G6PD has previously been reported in individuals with G6PD deficiency and is also known as G6PD Kerala, G6PD Kalyan, G6PD Kerala Kalyan, G6PD Jamnagar, and G6PD Rohini in the literature [(PMID: 15996881, 1303182, 30097005,16528451, 15315792, 27880809, 27535533, 33069889]. The c.949G>A p.(Glu317Lys) variant in G6PD is reported as Class III variant according to WHO classification and associated with moderate G6PD deficiency (10-60% enzyme activity) and hemolysis with stressors only [PMID:15996881,22293322]. Based on available evidence this maternally inherited hemizygous c.949G>A p.(Glu317Lys) variant identified in the G6PD gene is classified as Pathogenic.

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

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004810370.1

#	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: Oct 26, 2024

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