NM_000402.4(G6PD):c.653C>T (p.Ser218Phe) AND G6PD deficiency

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Oct 5, 2023
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:: RCV000445579.15

Allele description [Variation Report for NM_000402.4(G6PD):c.653C>T (p.Ser218Phe)]

NM_000402.4(G6PD):c.653C>T (p.Ser218Phe)

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.653C>T (p.Ser218Phe)

Other names:

G6PD, SER188PHE; G6PD Birmingham; G6PD Cagliari; G6PD Dallas; G6PD Mediterranean; G6PD Panama; G6PD Sassari

HGVS:

NC_000023.11:g.154534419G>A
NG_009015.2:g.18154C>T
NM_000402.4:c.653C>T
NM_001042351.3:c.563C>T
NM_001360016.2:c.563C>TMANE SELECT
NP_000393.4:p.Ser218Phe
NP_001035810.1:p.Ser188Phe
NP_001035810.1:p.Ser188Phe
NP_001035810.1:p.Ser188Phe
NP_001346945.1:p.Ser188Phe
NC_000023.10:g.153762634G>A
NM_000402.3:c.653C>T
NM_001042351.1:c.563C>T
NM_001042351.2:c.563C>T
NM_001042351.2:c.[563C>T]
NM_001042351.3:c.563C>T
NM_001360016.2:c.563C>T

Protein change:

S188F; SER188PHE

Links:

Genetic Testing Registry (GTR): GTR000613302; OMIM: 305900.0006; dbSNP: rs5030868

NCBI 1000 Genomes Browser:

rs5030868

Molecular consequence:

NM_000402.4:c.653C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001042351.3:c.563C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001360016.2:c.563C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: G6PD deficiency
Synonyms:: Glucose 6 phosphate dehydrogenase deficiency; G6PD A-
Identifiers:: MONDO: MONDO:0005775; MedGen: C2939465

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000106042	FirmaLab, FirmaLab	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV000915299	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Pathogenic (Jan 18, 2023)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 24586352, 19594365, 22906047, 23479361, 3393536, 24460025 Citation Link,
SCV004122524	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 5, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 3393536, 1978555, 22906047, 36703223, 35753512 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000106042

FirmaLab, FirmaLab

no assertion criteria provided

Pathogenic

germline

clinical testing

SCV000915299

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSLVariantClassificationCriteria RUGD 01 April 2020)

Pathogenic
(Jan 18, 2023)

unknown

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV004122524

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Oct 5, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	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	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A population survey of the glucose-6-phosphate dehydrogenase (G6PD) 563C>T (Mediterranean) mutation in Afghanistan.

Jamornthanyawat N, Awab GR, Tanomsing N, Pukrittayakamee S, Yamin F, Dondorp AM, Day NP, White NJ, Woodrow CJ, Imwong M.

PLoS One. 2014;9(2):e88605. doi: 10.1371/journal.pone.0088605.

PubMed [citation]

PMID:: 24586352
PMCID:: PMC3931629

G6PD Mediterranean S188F codon mutation is common among Saudi sickle cell patients and increases the risk of stroke.

Hellani A, Al-Akoum S, Abu-Amero KK.

Genet Test Mol Biomarkers. 2009 Aug;13(4):449-52. doi: 10.1089/gtmb.2009.0011.

PubMed [citation]

PMID:: 19594365

See all PubMed Citations (9)

Details of each submission

From FirmaLab, FirmaLab, SCV000106042.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing (GTR000327733)	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	(GTR000327733)	not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000915299.2

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

Description

The G6PD c.563C>T (p.Ser188Phe) missense variant, also referred to as G6PD Mediterranean, results in the substitution of serine at amino acid position 188 with phenylalanine. Across a selection of the available literature, the variant has been identified in a homozygous state in six probands, in a hemizygous state in 109 probands and in a heterozygous state in 25 probands (PMID: 19594365; 22906047; 23479361; 24460025; 24586352). The c.563C>T variant was reported in seven of 42 controls in a presumed heterozygous state and is reported at a frequency of 0.017450 in the South Asian population of the Genome Aggregation Database. The c.563C>T variant resulted in 0-7% residual enzyme activity in red blood cells compared to wild type and caused decreased thermostability and reduced catalytic activity (PMID: 3393536). Based on the collective evidence, the c.563C>T (p.Ser188Phe) variant is classified as pathogenic for glucose-6-phosphate dehydrogenase deficiency.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004122524.1

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

Description

Variant summary: G6PD c.653C>T (p.Ser218Phe) results in a non-conservative amino acid change located in the Glucose-6-phosphate dehydrogenase, C-terminal domain (IPR022675) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0026 in 183257 control chromosomes in the gnomAD database, including 6 homozygotes. This variant has a high frequency in South Asian population (0.017) in gnomAD. c.653C>T (Also known as G6PD Mediterranean) is a common cause of G6PD deficiency in the Mediterranean area, the Middle East and the India subcontinent (Kurdi-Haidar_1990). c.653C>T has been reported in the literature in multiple individuals affected with severe Glucose 6 Phosphate Dehydrogenase Deficiency (Kurdi-Haidar_1990), neonatal hyperbilirubinaemia (Moiz_2012) and hemolytic anemia (examples: Vulliamy_1988, Similuk_2022, and Naofal_2023). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Vulliamy_1988). The following publications have been ascertained in the context of this evaluation (PMID: 36703223, 35753512, 22906047, 3393536, 1978555). Thirty submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was 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

Last Updated: Oct 13, 2024

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