NM_000402.4(G6PD):c.896G>A (p.Cys299Tyr) AND Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Aug 12, 2022
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:: RCV000011156.12

Allele description [Variation Report for NM_000402.4(G6PD):c.896G>A (p.Cys299Tyr)]

NM_000402.4(G6PD):c.896G>A (p.Cys299Tyr)

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.896G>A (p.Cys299Tyr)

Other names:

G6PD, CYS269TYR; G6PD Aviero

HGVS:

NC_000023.11:g.154533634C>T
NG_009015.2:g.18939G>A
NM_000402.4:c.896G>A
NM_001042351.3:c.806G>A
NM_001360016.2:c.806G>AMANE SELECT
NP_000393.4:p.Cys299Tyr
NP_001035810.1:p.Cys269Tyr
NP_001346945.1:p.Cys269Tyr
NC_000023.10:g.153761849C>T
NM_001042351.1:c.806G>A

Protein change:

C269Y; CYS269TYR

Links:

OMIM: 305900.0053; dbSNP: rs137852346

NCBI 1000 Genomes Browser:

rs137852346

Molecular consequence:

NM_000402.4:c.896G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042351.3:c.806G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001360016.2:c.806G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000031383	OMIM	no assertion criteria provided	Pathogenic (Feb 15, 2000)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002304367	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 20, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10666231, 28492532
SCV002599229	Dunham Lab, University of Washington	criteria provided, single submitter (Bayesian ACMG Guidelines, 2018)	Likely pathogenic (Aug 12, 2022)	de novo	curation	PubMed (2) [See all records that cite these PMIDs] 10666231, 29300386

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000031383

OMIM

no assertion criteria provided

Pathogenic
(Feb 15, 2000)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV002304367

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 20, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002599229

Dunham Lab, University of Washington

criteria provided, single submitter

(Bayesian ACMG Guidelines, 2018)

Likely pathogenic
(Aug 12, 2022)

de novo

curation

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	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	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Glucose-6-phosphate dehydrogenase aveiro: a de novo mutation associated with chronic nonspherocytic hemolytic anemia.

Costa E, Cabeda JM, Vieira E, Pinto R, Pereira SA, Ferraz L, Santos R, Barbot J.

Blood. 2000 Feb 15;95(4):1499-501.

PubMed [citation]

PMID:: 10666231

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000031383.4

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

Description

In a boy born in Aveiro, Portugal with severe chronic hemolytic anemia (300908) present from birth, Costa et al. (2000) found that the undetectable G6PD activity was caused by a G-to-A transition at nucleotide position 806 of the G6PD gene resulting in a cys269-to-tyr (C269Y) amino acid substitution. This mutation, which was designated G6PD Aveiro, was not detected in his mother or sister. By the age of 5 years, the patient had had 6 episodes of severe acute intravascular hemolysis that required hospitalization and erythrocyte transfusion. The spleen was palpable 6 cm below the left costal margin. Costa et al. (2000) pointed out that G6PD mutants causing class 1 variants (the most severe forms of the disease) cluster within exon 10, in a region that, at the protein level, is believed to be involved in dimerization. The mutation in this new class 1 variant maps to exon 8. Mutant and normal alleles were found in both hematopoietic and buccal cells, indicating mosaicism.

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

From Invitae, SCV002304367.3

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

Description

This sequence change replaces cysteine with tyrosine at codon 269 of the G6PD protein (p.Cys269Tyr). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and tyrosine. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. This variant has been observed in individual(s) with G6PD deficiency (PMID: 10666231). ClinVar contains an entry for this variant (Variation ID: 10412). This variant is not present in population databases (ExAC no frequency).

#	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 Dunham Lab, University of Washington, SCV002599229.1

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

Description

Variant found in hemizygote with G6PD deficiency and CNSHA (PP4). Mother and sister have normal G6PD activity and do not carry variant, so presumed de novo (PM6). Undetectable activity in red blood cells and granulocytes (PS3). Not found in gnomAD (PM2). Post_P 0.988 (odds of pathogenicity 729.3, Prior_P 0.1).

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

Last Updated: Mar 30, 2024

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