NM_001360016.2(G6PD):c.1360C>T (p.Arg454Cys) AND Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Jan 31, 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:: RCV000174032.31

Allele description [Variation Report for NM_001360016.2(G6PD):c.1360C>T (p.Arg454Cys)]

NM_001360016.2(G6PD):c.1360C>T (p.Arg454Cys)

Gene:

G6PD:glucose-6-phosphate dehydrogenase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq28

Genomic location:

Preferred name:

NM_001360016.2(G6PD):c.1360C>T (p.Arg454Cys)

Other names:

G6PD Chinese-2; G6PD Kalo; G6PD Maewo; G6PD Union

HGVS:

NC_000023.11:g.154532390G>A
NG_009015.2:g.20183C>T
NM_000402.4:c.1450C>T
NM_001042351.3:c.1360C>T
NM_001360016.2:c.1360C>TMANE SELECT
NP_000393.4:p.Arg484Cys
NP_001035810.1:p.Arg454Cys
NP_001035810.1:p.Arg454Cys
NP_001035810.1:p.Arg454Cys
NP_001346945.1:p.Arg454Cys
NC_000023.10:g.153760605G>A
NM_001042351.1:c.1360C>T
NM_001042351.2:c.1360C>T

Protein change:

R454C

Links:

dbSNP: rs398123546

NCBI 1000 Genomes Browser:

rs398123546

Molecular consequence:

NM_000402.4:c.1450C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001042351.3:c.1360C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001360016.2:c.1360C>T - 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
SCV000647799	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10221015, 12497642, 22293322, 26823837, 16088936, 28492532
SCV000996202	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 3, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002023783	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 1, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002516410	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2019)	Pathogenic (May 4, 2022)	germline	clinical testing	Citation Link,
SCV002583713	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 13, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002599390	Dunham Lab, University of Washington	criteria provided, single submitter (Bayesian ACMG Guidelines, 2018)	Pathogenic (Aug 12, 2022)	inherited	curation	PubMed (21) [See all records that cite these PMIDs] 12497642, 8611726, 4721339, 7825590, 16143877, 11793482, 15727905, 33636823, 1459579, 4392654, 8447319, 16329560, 31863082, 4435794, 8244337, 30045279, 7577654, 9233561, 34620237, 35840819, 29300386
SCV002767241	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 6, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12105841, 12497642, 16088936, 22293322, 25741868

Help

Summary from all submissions

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

Citations

PubMed

Molecular basis of glucose-6-phosphate dehydrogenase deficiency among Filipinos.

Silao CL, Shirakawa T, Nishiyama K, Padilla C, Matsuo M.

Pediatr Int. 1999 Apr;41(2):138-41.

PubMed [citation]

PMID:: 10221015

Molecular epidemiological investigation of G6PD deficiency by a gene chip among Chinese Hakka of southern Jiangxi province.

Hu R, Lin M, Ye J, Zheng BP, Jiang LX, Zhu JJ, Chen XH, Lai M, Zhong TY.

Int J Clin Exp Pathol. 2015;8(11):15013-8.

PubMed [citation]

PMID:: 26823837
PMCID:: PMC4713623

See all PubMed Citations (28)

Details of each submission

From Invitae, SCV000647799.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 454 of the G6PD protein (p.Arg454Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with G6PD deficiency (PMID: 10221015, 12497642, 22293322, 26823837). ClinVar contains an entry for this variant (Variation ID: 93493). 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: 16088936). 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 Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV000996202.1

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

Description

This variant is also known in the literature as c.1360C>T (p.Arg454Cys) and is also commonly described as the "Union" or "Maewo" variant. In the gnomAD population database this variant is present in the heterozygous state at a frequency of 0.014% (29/2038745)and the hemizygous state in 5 individuals. This variant has been reported in the hemizygous state in many individuals affected with G6PD deficiency in different ethnic groups (PMID: 12497642, 26823837, 22293322, 10221015) and is classified by multiple clinical laboratories as pathogenic in the ClinVar database (Variation ID: 93493). Functional in vitro studies demonstrate this variant impacts protein thermostability and decreases catalytic efficiency of the enzyme (PMID: 16088936). Based on the overall evidence, the c.1450C>T (p.Arg484Cys) variant was classified as pathogenic.

#	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

From Revvity Omics, Revvity, SCV002023783.3

#	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

From Mendelics, SCV002516410.1

#	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 Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV002583713.1

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

Description

PS3, PS4, PM5, PP3

#	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, SCV002599390.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (21)

Description

Variant found in unrelated hemizygotes with deficiency, some with jaundice, anemia, and favism (PS4_M, PP4). In one family, variant segregates with deficiency over multiple generations (PP1). Decreased activity in red blood cells of hemizygotes (0-21%) (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	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, SCV002767241.1

#	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 deficient hemolytic anemia (favism) (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) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (12 heterozygotes, 1 homozygote, 5 hemizygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (0 Heterozygotes, 0 Homozygotes, 1 Hemizygote). (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 (PDB). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Two alternative nucleotide changes have been reported as pathogenic (ClinVar, PMID: 12105841, 12497642). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is one of the most common pathogenic variants, known as the Union or Maewo variant, reported in the literature. (ClinVar, PMID: 22293322). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been shown to impact on protein thermostability and decreases catalytic efficiency of the enzyme (PMID: 16088936). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (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

Last Updated: Apr 20, 2024

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