chrX-154534419-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 8P and 2B. PP5_Very_StrongBP4BS1_Supporting

The NM_001360016.2(G6PD):​c.563C>T​(p.Ser188Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00141 in 1,209,752 control chromosomes in the GnomAD database, including 23 homozygotes. There are 859 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00072 ( 2 hom., 37 hem., cov: 23)
Exomes 𝑓: 0.0015 ( 21 hom. 822 hem. )

Consequence

G6PD
NM_001360016.2 missense

Scores

5
7
4

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:51O:3

Conservation

PhyloP100: 5.54
Variant links:
Genes affected
G6PD (HGNC:4057): (glucose-6-phosphate dehydrogenase) This gene encodes glucose-6-phosphate dehydrogenase. This protein is a cytosolic enzyme encoded by a housekeeping X-linked gene whose main function is to produce NADPH, a key electron donor in the defense against oxidizing agents and in reductive biosynthetic reactions. G6PD is remarkable for its genetic diversity. Many variants of G6PD, mostly produced from missense mutations, have been described with wide ranging levels of enzyme activity and associated clinical symptoms. G6PD deficiency may cause neonatal jaundice, acute hemolysis, or severe chronic non-spherocytic hemolytic anemia. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PP5
Variant X-154534419-G-A is Pathogenic according to our data. Variant chrX-154534419-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 100057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154534419-G-A is described in Lovd as [Pathogenic]. Variant chrX-154534419-G-A is described in Lovd as [Pathogenic]. Variant chrX-154534419-G-A is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.012398928). . Strength limited to SUPPORTING due to the PP5.
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00148 (1624/1097898) while in subpopulation MID AF= 0.0435 (180/4135). AF 95% confidence interval is 0.0383. There are 21 homozygotes in gnomad4_exome. There are 822 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
G6PDNM_001360016.2 linkc.563C>T p.Ser188Phe missense_variant Exon 6 of 13 ENST00000393562.10 NP_001346945.1
G6PDNM_000402.4 linkc.653C>T p.Ser218Phe missense_variant Exon 6 of 13 NP_000393.4 P11413-3
G6PDNM_001042351.3 linkc.563C>T p.Ser188Phe missense_variant Exon 6 of 13 NP_001035810.1 P11413-1A0A384NL00

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
G6PDENST00000393562.10 linkc.563C>T p.Ser188Phe missense_variant Exon 6 of 13 1 NM_001360016.2 ENSP00000377192.3 P11413-1

Frequencies

GnomAD3 genomes
AF:
0.000733
AC:
82
AN:
111798
Hom.:
2
Cov.:
23
AF XY:
0.00109
AC XY:
37
AN XY:
34036
show subpopulations
Gnomad AFR
AF:
0.000130
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00604
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.0153
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0126
Gnomad NFE
AF:
0.000208
Gnomad OTH
AF:
0.00468
GnomAD3 exomes
AF:
0.00255
AC:
468
AN:
183257
Hom.:
6
AF XY:
0.00375
AC XY:
254
AN XY:
67757
show subpopulations
Gnomad AFR exome
AF:
0.000228
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00601
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0173
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000770
Gnomad OTH exome
AF:
0.00574
GnomAD4 exome
AF:
0.00148
AC:
1624
AN:
1097898
Hom.:
21
Cov.:
32
AF XY:
0.00226
AC XY:
822
AN XY:
363276
show subpopulations
Gnomad4 AFR exome
AF:
0.000303
Gnomad4 AMR exome
AF:
0.0000284
Gnomad4 ASJ exome
AF:
0.00547
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0189
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000189
Gnomad4 OTH exome
AF:
0.00323
GnomAD4 genome
AF:
0.000724
AC:
81
AN:
111854
Hom.:
2
Cov.:
23
AF XY:
0.00108
AC XY:
37
AN XY:
34102
show subpopulations
Gnomad4 AFR
AF:
0.000130
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00604
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.0149
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000208
Gnomad4 OTH
AF:
0.00462
Alfa
AF:
0.00139
Hom.:
63
Bravo
AF:
0.000559
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000692
AC:
2
ESP6500AA
AF:
0.000522
AC:
2
ESP6500EA
AF:
0.000743
AC:
5
ExAC
AF:
0.00310
AC:
376
EpiCase
AF:
0.00147
EpiControl
AF:
0.00119

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:51Other:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:26
Nov 02, 2023
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 14, 2014
Courtagen Diagnostics Laboratory, Courtagen Life Sciences
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 14, 2018
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Centogene AG - the Rare Disease Company
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 08, 2023
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Oct 28, 2024
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Criteria applied: PS3,PS4,PP3,PP4 -

Jan 17, 2020
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 20, 2023
Neuberg Centre For Genomic Medicine, NCGM
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The missense variant c.563C>T(p.Ser188Phe) in G6PD gene has been observed in individual(s) with G6PD deficiency (Thedsawad A, et. al., 2022;Arunachalam AK, et. al., 2020; AlJaouni et.al., 2011; Jamornthanyawat et. al., 2014). Experimental studies have shown that this missense change affects G6PD function (Molouet. al., 2014). It is commonly reported in individuals of Mediterranean, Middle Eastern, or Indian ancestry (AlJaouni et. al., 2011;Jamornthanyawat et. al., 2014). The observed variant has been reported with allele frequency of 0.2 % in gnomAD database. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). Computational evidence (Polyphen -Benign , SIFT - damaging and MutationTaster -disease causing) predicts conflicting evidence on protein structure and function for this variant. The amino acid change p.Ser188Phe in G6PD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 188 is changed to a Phe changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

Jun 06, 2015
Counsyl
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 17, 2023
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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 anaemia (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) 0200 - Variant is predicted to result in a missense amino acid change from serine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (203 heterozygotes, 6 homozygotes, 256 hemizygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated glucose-6-phosphate dehydrogenase NAD binding domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is reported as one of the most common severe pathogenic variants in this gene (ClinVar, LOVD, PMID: 27853304). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. The variant has been shown to result in highly impaired enzyme activity (PMID: 3393536, PMID: 7211845). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Aug 12, 2022
Dunham Lab, University of Washington
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation

Variant found in unrelated hemizygotes with deficiency, many with anemia, jaundice, and favism, and some with CNSHA (PS4_M, PP4). Phenotype transmitted with variant from mother to son (PP1). Decreased activity in red blood cells (0-33%) (PS3). Predicted to be deleterious by REVEL and SIFT (PP3). Reported as pathogenic by multiple clinical testing groups (PP5). Not found in gnomAD (PM2). Post_P 0.994 (odds of pathogenicity 1516, Prior_P 0.1). -

Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 188 of the G6PD protein (p.Ser188Phe). This variant is present in population databases (rs5030868, gnomAD 1.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with G6PD deficiency (PMID: 1978554, 8611726, 15315792, 16119988, 22018328, 24586352). It is commonly reported in individuals of Mediterranean, Middle Eastern, or Indian ancestry (PMID: 1978554, 8611726, 15315792, 16119988, 22018328, 24586352). ClinVar contains an entry for this variant (Variation ID: 100057). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 3393536, 22906047, 24460025). For these reasons, this variant has been classified as Pathogenic. -

Dec 30, 2017
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: curation

- -

Jul 22, 2021
Genome-Nilou Lab
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 28, 2019
Mendelics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 23, 2024
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

A heterozygous variant in exon 6 of the G6PD gene that results in the amino acid substitution of Phenylalanine for Serine at codon 188 was detected. The observed variant c.563C>T (p.Ser188Phe) was previously been reported in the 1000 genomes, gnomAD and TOPMed databases with MAF of 0.0833%, 0.1479% and 0.0559% respectively. The in silico prediction of the variant is damaging by SIFT, FATHMM and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic. -

Sep 01, 2022
3billion, Medical Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v2.1.1 dataset. However, this variant is the most common cause of G6PD deficiency in the Mediterranean area, the Middle East and the India subcontinent (ClinVar ID: VCV000100057). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 22906047 , 24460025 , 3393536). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.81; 3Cnet: 0.49). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Aug 02, 2022
MGZ Medical Genetics Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 31, 2023
New York Genome Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 02, 2024
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 05, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Lifecell International Pvt. Ltd
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant in exon 6 of the G6PD gene results in the amino acid substitution from Serine to Phenylalanine at codon 188 (p.Ser188Phe) with the sequence change of c.653C>T (NM_000402.4). This variant was observed in a proband with decreased level of G6PD enzyme (<2.4 U/dL) which was screened for advanced newborn screening with confirmatory genetic reflex testing at lifecell diagnostics. This variant is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT are damaging. This variant has previously been reported for Anemia, Nonspherocytic Hemolytic, Due to G6pd Deficiency by T J Vulliamy et al., 1988. 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 has been reported six individuals in homozygous condition, in 109 individuals in hemizygous condition and 25 individuals in heterozygous conditions. (Hellani et al. 2009; PMID: 19594365), (Moiz et al. 2012; PMID: 22906047), (Santana et al. 2013; PMID: 23479361), (Molou et al. 2014; PMID: 24460025) and (Jamornthanyawat et al. 2014; PMID: 24586352). -

Jul 27, 2022
Institute of Immunology and Genetics Kaiserslautern
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG Criteria: PS3, PS4, PP3, PP5; Variant was found in hemizygous state. -

May 24, 2023
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PS3, PS4, PM1, PP5 -

Aug 13, 2013
UCLA Clinical Genomics Center, UCLA
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:13
Sep 30, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The G6PD c.563C>T; p.Ser188Phe variant (rs5030868), also known as G6PD Mediterranean, is reported in the literature in multiple individuals affected with hemolytic anemia, hyperbilirubinemia and G6PD deficiency (Hellani 2009, Jamornthanyawat 2014, Kaplan 1997, Moiz 2012, Molou 2014, Vulliamy 1988). Functional analyses of the variant protein shows decreased enzyme activity, increased affinity for G6P and decreased in vitro thermostability (Moiz 2012, Molou 2014, Vulliamy 1988). This variant is reported in ClinVar (Variation ID: 100057). This variant is found predominantly in the South Asian population with an allele frequency of 1.7% (331/19,078 alleles, including 4 homozygotes and 211 hemizygotes) in the Genome Aggregation Database. The serine at codon 188 is moderately conserved, but computational analyses predict that this variant is deleterious (REVEL: 0.811). Based on available information, this variant is considered to be pathogenic. References: Hellani A et al. G6PD Mediterranean S188F codon mutation is common among Saudi sickle cell patients and increases the risk of stroke. Genet Test Mol Biomarkers. 2009 Aug;13(4):449-52. Jamornthanyawat N et al. A population survey of the glucose-6-phosphate dehydrogenase (G6PD) 563C>T (Mediterranean) mutation in Afghanistan. PLoS One. 2014 Feb 21;9(2):e88605. Kaplan M et al. Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: a dose-dependent genetic interaction crucial to neonatal hyperbilirubinemia. Proc Natl Acad Sci U S A. 1997 Oct 28;94(22):12128-32. Moiz B et al. Neonatal hyperbilirubinemia in infants with G6PD c.563C > T Variant. BMC Pediatr. 2012 Aug 20;12:126. Molou E et al. Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency in Greek newborns: the Mediterranean C563T mutation screening. Scand J Clin Lab Invest. 2014 Apr;74(3):259-63. Vulliamy TJ et al. Diverse point mutations in the human glucose-6-phosphate dehydrogenase gene cause enzyme deficiency and mild or severe hemolytic anemia. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5171-5. -

Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

G6PD: PP1:Strong, PS4, PS3:Moderate -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 15, 2017
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 08, 2023
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 29, 2023
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 23, 2020
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 17, 2022
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 05, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published functional studies demonstrate decreased enzyme activity in circulating erythrocytes, increased affinity for G6P, and decreased in vitro thermostability (Vulliamy et al., 1998); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23479361, 27535533, 31152693, 33413378, 31322791, 24460025, 3393536, 27884173, 19594365, 24586352, 1978555, 25548459, 28492530, 8611726, 28492532, 27853304, 27108201, 30097005, 31863082, 33069889, 31019026, 31980526, 34272389, 34426522, 33072997, 33083013, 30755392, 12215013, 32535712, 32860008, 33726816, 1978554, 22906047) -

G6PD deficiency Pathogenic:3
Oct 05, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jan 18, 2023
Illumina Laboratory Services, Illumina
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

-
FirmaLab, FirmaLab
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Malaria, susceptibility to;C2720289:Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:2
May 31, 2016
Division of Human Genetics, Children's Hospital of Philadelphia
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Malaria, susceptibility to Pathogenic:2
Mar 16, 2021
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 28, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1
Dec 14, 2016
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

G6PD deficient hemolytic anemia Pathogenic:1
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Centogene AG - the Rare Disease Company
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hemolytic anemia, G6PD deficient (favism) Pathogenic:1
Apr 14, 2020
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is also known as c.563C>T, p.Ser188Phe (using the alternative transcripts NM_001042351.3 and NM_001360016.2).This alteration has been previously reported as hemizygous change in patients with hemolytic anemia associated with Glucose 6-phosphate deficiency (PMID: 28067620, 24586352, 11445808, 12768444). Functional studies demonstrate decreased enzyme activity in the circulating erythrocytes of individuals with this variant, increased affinity for G6P and decreased in vitro thermostability (PMID: 9342374, 3393536). It is present in the gnomAD population database at a frequency of 0.23% with 471/204697 in heterozygous state, 6/204697 in homozygous state and 256/204697 in hemizygous state. In silico analyses support a deleterious effect of the c.653C>T (p.Ser218Phe) variant on protein function. Based on the available evidence, the c.653C>T (p.Ser218Phe) variant is classified as Pathogenic. -

G6PD-related disorder Pathogenic:1
May 30, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The G6PD c.563C>T variant is predicted to result in the amino acid substitution p.Ser188Phe. This variant, commonly referred to as the "Mediterranean" allele, has been reported to be causative for glucose-6-phosphate dehydrogenase (G6PD) deficiency (see for examples Vulliamy et al. 1988. PubMed ID: 3393536; Yusoff et al. 2002. PubMed ID: 12215013; Moiz et al. 2012. PubMed ID: 22906047). This variant is reported in 1.7% of alleles in individuals of South Asian descent and with a global allele frequency of 0.17% including hundreds of hemizygous individuals and several homozygous individuals. This variant is interpreted as pathogenic. -

See cases Pathogenic:1
Mar 28, 2023
Institute of Human Genetics, University Hospital Muenster
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG categories: PS3,PM1,PP3,PP5,BP1 -

G6PD SASSARI Other:1
May 11, 2018
OMIM
Significance: other
Review Status: no assertion criteria provided
Collection Method: literature only

- -

G6PD CAGLIARI Other:1
May 11, 2018
OMIM
Significance: other
Review Status: no assertion criteria provided
Collection Method: literature only

- -

G6PD MEDITERRANEAN Other:1
May 11, 2018
OMIM
Significance: other
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.32
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Pathogenic
0.45
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.96
D;D;D;.;D;.;D
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.95
.;.;D;D;D;D;D
MetaRNN
Benign
0.012
T;T;T;T;T;T;T
MetaSVM
Pathogenic
0.96
D
MutationAssessor
Pathogenic
3.4
M;M;M;M;.;.;.
PrimateAI
Benign
0.36
T
PROVEAN
Uncertain
-4.2
.;.;D;D;D;D;D
REVEL
Pathogenic
0.81
Sift
Uncertain
0.017
.;.;D;D;D;D;D
Sift4G
Uncertain
0.0080
D;.;D;T;.;.;.
Polyphen
0.022
B;B;B;.;.;.;.
Vest4
0.56
MVP
0.99
MPC
0.20
ClinPred
0.13
T
GERP RS
5.7
Varity_R
0.90
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs5030868; hg19: chrX-153762634; COSMIC: COSV63704212; COSMIC: COSV63704212; API