NM_000402.4(G6PD):c.934G>C (p.Asp312His) AND Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Jan 19, 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:: RCV000180200.32

Allele description [Variation Report for NM_000402.4(G6PD):c.934G>C (p.Asp312His)]

NM_000402.4(G6PD):c.934G>C (p.Asp312His)

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.934G>C (p.Asp312His)

Other names:

G6PD, ASP282HIS; G6PD Athens-like; G6PD Ferrara-II; G6PD Lodi; G6PD Modena; G6PD Seattle

HGVS:

NC_000023.11:g.154533596C>G
NG_009015.2:g.18977G>C
NM_000402.4:c.934G>C
NM_001042351.3:c.844G>C
NM_001360016.2:c.844G>CMANE SELECT
NP_000393.4:p.Asp312His
NP_001035810.1:p.Asp282His
NP_001035810.1:p.Asp282His
NP_001346945.1:p.Asp282His
NC_000023.10:g.153761811C>G
NM_000402.3:c.934G>C
NM_001042351.1:c.844G>C
NM_001042351.2:c.844G>C
NM_001042351.3:c.844G>C
NM_001360016.2:c.844G>C

Protein change:

D282H; ASP282HIS

Links:

OMIM: 305900.0010; dbSNP: rs137852318

NCBI 1000 Genomes Browser:

rs137852318

Molecular consequence:

NM_000402.4:c.934G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001042351.3:c.844G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001360016.2:c.844G>C - 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
SCV000236504	Courtagen Diagnostics Laboratory, Courtagen Life Sciences	criteria provided, single submitter (Courtagen Life Sciences Classifications)	Pathogenic (Apr 10, 2014)	germline	clinical testing	Citation Link,
SCV000647803	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 19, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 2912069, 5305539, 7947250, 8807321, 7806085, 7947239, 28492532
SCV001443774	Lifecell International Pvt. Ltd	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002516414	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2019)	Pathogenic (May 4, 2022)	germline	clinical testing	Citation Link,
SCV002587049	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill - CSER_NCGENES_2	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 20, 2021)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV002599347	Dunham Lab, University of Washington	criteria provided, single submitter (Bayesian ACMG Guidelines, 2018)	Pathogenic (Aug 12, 2022)	maternal	curation	PubMed (19) [See all records that cite these PMIDs] 8447319, 25536053, 7803800, 24134566, 33636823, 7959686, 16143877, 5844610, 12064920, 5673160, 7947250, 10782016, 30096395, 12367584, 7947239, 34620237, 9233561, 21637675, 29300386
SCV002768052	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 (5) [See all records that cite these PMIDs] 11146567, 12064920, 25536053, 30096395, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	maternal	yes	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	1	not provided	not provided	1	not provided	research
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
Asian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Two point mutations are responsible for G6PD polymorphism in Sardinia.

De Vita G, Alcalay M, Sampietro M, Cappelini MD, Fiorelli G, Toniolo D.

Am J Hum Genet. 1989 Feb;44(2):233-40.

PubMed [citation]

PMID:: 2912069
PMCID:: PMC1715414

Characterization of glucose-6-phosphate dehydrogenase variants. I. Occurrence of a G6PD Seattle-like variant in Sardinia and its interaction with the G6PD Mediterranean variant.

Lenzerini L, Meera Khan P, Filippi G, Rattazzi MC, Ray AK, Siniscalco M.

Am J Hum Genet. 1969 Mar;21(2):142-53. No abstract available.

PubMed [citation]

PMID:: 5305539
PMCID:: PMC1706428

See all PubMed Citations (26)

Details of each submission

From Courtagen Diagnostics Laboratory, Courtagen Life Sciences, SCV000236504.2

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000647803.7

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

Description

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 282 of the G6PD protein (p.Asp282His). This variant is present in population databases (rs137852318, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with G6PD deficiency (PMID: 2912069, 5305539, 7806085, 7947239, 7947250, 8807321). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10372). 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) performed at Invitae indicates that this missense variant is expected to disrupt G6PD protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects G6PD function (PMID: 7806085, 7947239). 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 Lifecell International Pvt. Ltd, SCV001443774.1

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

Description

This variant in exon 8 of the G6PD gene results in the amino acid substitution from Aspartic acid to Histidine at codon 312 (p.Asp312His) with the sequence change of c.934G>C (NM_000402.4). This variant was observed in a proband with decreased level of G6PD enzyme (<3.8 U/dL) which was screened for advanced newborn screening with confirmatory genetic reflex testing at lifecell diagnostics. The observed variant has a minor allele frequency of 0.0007040% in gnomAD database. 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 mild to moderate G6PD deficiency (0.10-0.60 normal activity), with intermittent hemolysis. The G6PD c.934G>C; p.Asp312His variant also referred to as c.844G>C; p.Asp282His, commonly known as G6PD-Ferrara II or Lodi or Modena or Seattle in the literature. This variant has previously been reported for Glucose-6- phosphate dehydrogenase (G6PD) deficieny by (Cappellini MD et al., 1994, PMID: 7947250; Alfinito F et al., 1994, PMID: 7947239; Rudilla F et al., 2019, PMID: 31681265)

#	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		1	not provided	not provided	not provided

From Mendelics, SCV002516414.1

#	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 UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill - CSER_NCGENES_2, SCV002587049.1

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

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

From Dunham Lab, University of Washington, SCV002599347.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (19)

Description

Variant found in unrelated hemizygotes with deficiency, some with anemia, favism, and jaundice (PS4_M, PP4). In one family, hemizygous brothers have deficiency and heterozygous mother has decreased G6PD activity (PP1). Decreased activity in red blood cells (3-45%) and when expressed in E. coli (PS3). Predicted to be damaging by SIFT, probably damaging by PolyPhen (PP3). Below expected carrier frequency in gnomAD (PM2). Reported as pathogenic by multiple clinical testing groups (PP5). Post_P 0.999 (odds of pathogenicity 6563, 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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768052.2

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

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 deficiency (MIM#300908). (I) 0109 - This gene is associated with X-linked recessive disease. Hemizygous males and homozygous females are commonly affected, however some heterozygous female carriers can also be affected depending on X inactivation. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to histidine. (I) 0251 - This variant is heterozygous. (I) 0310 - Variant is present in gnomAD (v2) >=0.001 and <0.01 for a dominant condition (89 heterozygotes, 0 homozygotes, 53 hemizygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated G6PD C-terminal domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is a well-known pathogenic allele also known as G6PD Seattle/Ferrara II/Modena/Athens-like (ClinVar, PMID: 11146567, 12064920, 25536053). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Enzyme activity in patient cells is reduced relative to wild type, and in vitro studies support abnormal protein function (PMID: 11146567, 12064920, 30096395). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I)

#	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

Last Updated: Nov 10, 2024

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