VCV000010367.37 - ClinVar

NM_000402.4(G6PD):c.577G>A (p.Gly193Ser)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(18)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000402.4(G6PD):c.577G>A (p.Gly193Ser)

Variation ID: 10367 Accession: VCV000010367.37

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq28 X: 154534495 (GRCh38) [ NCBI UCSC ] X: 153762710 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 27, 2017	Oct 8, 2024	Mar 20, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001360016.2:c.487G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001346945.1:p.Gly163Ser	missense
NM_000402.3:c.577G>A
NM_000402.4:c.577G>A	NP_000393.4:p.Gly193Ser	missense
NM_001042351.3:c.487G>A	NP_001035810.1:p.Gly163Ser	missense
NC_000023.11:g.154534495C>T
NC_000023.10:g.153762710C>T
NG_009015.2:g.18078G>A

... more HGVS ... less HGVS

Protein change

G163S, G193S

Other names

G6PD, GLY163SER
G6PD Mahidol

Canonical SPDI

NC_000023.11:154534494:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00000

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00004

Exome Aggregation Consortium (ExAC) 0.00005

Links

ClinGen: CA120953 OMIM: 305900.0005 dbSNP: rs137852314 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
G6PD		-	-	GRCh38 GRCh37	-	-

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
G6PD MAHIDOL	other (1)	no assertion criteria provided	May 24, 2017	RCV000011085.4
not specified	Pathogenic (1)	criteria provided, single submitter	Mar 9, 2017	RCV000507435.8
Anemia, nonspherocytic hemolytic, due to G6PD deficiency	Pathogenic/Likely pathogenic (10)	criteria provided, multiple submitters, no conflicts	Jan 21, 2024	RCV000282708.24
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 6, 2024	RCV000657881.10
Anemia, nonspherocytic hemolytic, due to G6PD deficiency Malaria, susceptibility to	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000763205.2
G6PD deficiency	Pathogenic (1)	criteria provided, single submitter	Sep 8, 2022	RCV002298440.1
Malaria, susceptibility to	Pathogenic (1)	criteria provided, single submitter	Mar 20, 2024	RCV003466846.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Mar 09, 2017)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000603774.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017
Pathogenic (Dec 03, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Anemia, nonspherocytic hemolytic, due to G6PD deficiency (X-linked inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001164403.1 First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020	Publications: PubMed (6) PubMed: 27880809‚ 2503817‚ 11499668‚ 15349799‚ 17959407‚ 8118045 Comment: The hemizygous p.Gly193Ser variant in G6PD was identified by our study in one individual with non-spherocytic hemolytic anemia due to G6PD deficiency. This variant has … (more) The hemizygous p.Gly193Ser variant in G6PD was identified by our study in one individual with non-spherocytic hemolytic anemia due to G6PD deficiency. This variant has been identified in 0.03657% (7/19142) of South Asian chromosomes, including 3 hemizygous individuals, and 0.01442% (2/13869) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137852314). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Although this variant has been seen in the general population, most individuals with non-spherocytic hemolytic anemia due to G6PD deficiency are asymptomatic. This variant has been reported pathogenic in ClinVar (Variation ID: 10367). The p.Gly193Ser variant in G6PD has been reported in 75 Southeast Asian individuals with G6PD Deficiency in the literature (PMID: 27880809, 2503817, 11499668, 15349799). The prevalence of this variant in affected individuals is significantly increased compared to the prevalence in large population studies, supporting pathogenicity. In vitro functional studies provide some evidence that the p.Gly193Ser variant may impact protein stability, activity, (PMID: 17959407, 8118045). In summary, the p.Gly193Ser variant is pathogenic. ACMG/AMP Criteria applied: PP3, PS3, PS4 (Richards 2015). (less)
Likely pathogenic (Apr 21, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Anemia, nonspherocytic hemolytic, due to G6PD deficiency Affected status: unknown Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV002059872.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022
Pathogenic (Jan 21, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Anemia, nonspherocytic hemolytic, due to G6PD deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000768478.7 First in ClinVar: Dec 06, 2016 Last updated: Feb 14, 2024	Publications: PubMed (11) PubMed: 28492532‚ 2503817‚ 11499668‚ 11793482‚ 21989994‚ 23926329‚ 26226515‚ 27880809‚ 8118045‚ 17959407‚ 22165289 Comment: This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 163 of the G6PD protein (p.Gly163Ser). … (more) This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 163 of the G6PD protein (p.Gly163Ser). This variant is present in population databases (rs137852314, gnomAD 0.04%). This missense change has been observed in individuals with glucose-6-phosphate dehydrogenase deficiency (PMID: 2503817, 11499668, 11793482, 21989994, 23926329, 26226515, 27880809). It is commonly reported in individuals of South Asian ancestry (PMID: 2503817, 11499668, 11793482, 21989994, 23926329, 26226515, 27880809). This variant is also known as G6PD Mahidol. ClinVar contains an entry for this variant (Variation ID: 10367). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects G6PD function (PMID: 8118045, 17959407, 22165289). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 20, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Malaria, susceptibility to Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004195393.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Feb 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Anemia, nonspherocytic hemolytic, due to G6PD deficiency (X-linked recessive inheritance) Affected status: no Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV003921875.2 First in ClinVar: May 06, 2023 Last updated: Jul 23, 2024	Publications: PubMed (4) PubMed: 17959407‚ 22171972‚ 25536053‚ 27880809 Comment: 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 … (more) 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 anemia (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 glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.001 for a recessive condition (5 heterozygotes, 3 hemizygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated NAD binding domain (Pfam). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternative missense change to aspartic acid has been described in individuals with severe G6PD deficiency (WHO class I; PMID: 27880809). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is one of the most common pathogenic G6PD variants in Thai and Burmese populations (WHO class II or III; ClinVar, PMID: 22171972, PMID: 25536053) (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant results in impaired folding and reduced protein stability (PMID: 17959407). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Mar 06, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000779644.5 First in ClinVar: Jul 09, 2018 Last updated: Sep 16, 2024	Comment: Published functional studies demonstrate G163S is less stable than wild type in both thermostability and urea-induced inactivation tests, and is also impaired in its folding … (more) Published functional studies demonstrate G163S is less stable than wild type in both thermostability and urea-induced inactivation tests, and is also impaired in its folding properties (PMID: 17959407); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20007901, 22165289, 29548282, 33069889, 34272389, 31323480, 11793482, 12215013, 36212142, 34659341, 33637102, 21989994, 27880809, 2503817, 29240263, 28356147, 28138089, 11499668, 1924316, 8956035, 15349799, 4435794, 1562739, 31589614, 34953813, 30097005, 29251006, 28376293, 17959407) (less)
Pathogenic (May 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Anemia, nonspherocytic hemolytic, due to G6PD deficiency (X-linked dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV005329626.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The observed missense c.487G>A(p.Gly163Ser) variant in G6PD gene has been reported previously in multiple individuals affected with glucose-6-phosphate dehydrogenase deficiency (Sarker SK, et al., 2016; … (more) The observed missense c.487G>A(p.Gly163Ser) variant in G6PD gene has been reported previously in multiple individuals affected with glucose-6-phosphate dehydrogenase deficiency (Sarker SK, et al., 2016; Li Q, et al., 2015; Nuchprayoon I, et al., 2002). Published functional studies demonstrate that this variant is less stable than wild type in both thermostability and urea-induced inactivation tests, and is also impaired in its folding properties (Huang Y, et al., 2008). The p.Gly163Ser variant has been reported with allele frequency of 0.004% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). Computational evidences (Polyphen - Probably damaging, SIFT - Tolerated and MutationTaster - Disease causing) predict conflicting evidence on protein structure and function for this variant. The amino acid change p.Gly163Ser in G6PD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 163 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Abnormality of blood and blood-forming tissues (present)
Pathogenic (Jun 02, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000331249.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=G6PD Number of individuals with the variant: 3 Sex: mixed
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Anemia, nonspherocytic hemolytic, due to G6PD deficiency Malaria, susceptibility to Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893825.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Anemia, nonspherocytic hemolytic, due to G6PD deficiency (X-linked recessive inheritance) Affected status: yes Allele origin: germline	Lifecell International Pvt. Ltd Accession: SCV001443095.1 First in ClinVar: Nov 14, 2020 Last updated: Nov 14, 2020	Comment: This variant in exon 6 of the G6PD gene results in the amino acid substitution from Glycine to Serine at codon 193 (p.Gly193Ser) with the … (more) This variant in exon 6 of the G6PD gene results in the amino acid substitution from Glycine to Serine at codon 193 (p.Gly193Ser) with the sequence change of c.577G>A (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. The observed variant has a minor allele frequency of 0.00004400% 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 II variant associated with moderate G6PD deficiency (<10% activity), with intermittent hemolysis. The G6PD c.577G>A; p.Gly193Ser variant, also referred to as c.487G>A; p.Gly163Ser. This variant has previously been reported for Glucose-6- phosphate dehydrogenase (G6PD) deficiency by (Sarker SK et al., 2016 PMID: 27880809; Li Q et al., 2015 PMID: 26226515; Narang A et al., 2020 PMID: 32906206.) (less) Sex: male
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Anemia, nonspherocytic hemolytic, due to G6PD deficiency Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002516419.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Pathogenic (Sep 08, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	G6PD deficiency Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002598619.1 First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022	Publications: PubMed (1) PubMed: 30674319 Comment: Variant summary: G6PD c.577G>A (p.Gly193Ser) results in a non-conservative amino acid change located in the Glucose-6-phosphate dehydrogenase, NAD-binding domain (IPR022674) of the encoded protein sequence. … (more) Variant summary: G6PD c.577G>A (p.Gly193Ser) results in a non-conservative amino acid change located in the Glucose-6-phosphate dehydrogenase, NAD-binding domain (IPR022674) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 181825 control chromosomes. c.577G>A, also known as G6PD Mahidol has been widely reported in the literature in multiple individuals affected with Glucose 6 Phosphate Dehydrogenase Deficiency and is considered among one of the most frequent mutations described among individuals of Vietnamese ancestry (example, Bancone_2019). These data indicate that the variant is very likely to be associated with disease. Mahidol variant has been shown to cause low or very low enzymatic activity in RBCs and is associated with relatively high hemolytic risk by 8-aminoquinolines treatment (cited in Bancone_2019). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Aug 12, 2022)	criteria provided, single submitter (Bayesian ACMG Guidelines, 2018) Method: curation	Anemia, nonspherocytic hemolytic, due to G6PD deficiency Affected status: yes Allele origin: unknown	Dunham Lab, University of Washington Accession: SCV002599331.1 First in ClinVar: Nov 13, 2022 Last updated: Nov 13, 2022	Publications: PubMed (20) PubMed: 23965028‚ 4435794‚ 25536053‚ 11793482‚ 18046504‚ 15727905‚ 27880809‚ 31863082‚ 8244337‚ 30045279‚ 4721339‚ 5081671‚ 16329560‚ 12497642‚ 16513531‚ 32425388‚ 16607506‚ 31489982‚ 25541721‚ 35840819 Comment: Variant found in unrelated hemizygotes with deficiency, some with jaundice, favism, and anemia (PS4_M, PP4). Decreased activity in red blood cells (0-30%) (PS3). Predicted to … (more) Variant found in unrelated hemizygotes with deficiency, some with jaundice, favism, and anemia (PS4_M, PP4). Decreased activity in red blood cells (0-30%) (PS3). Predicted to be damaging by SIFT and PolyPhen (PP3). Below expected carrier frequency in gnomAD (PM2). Reported as pathogenic by multiple clinical testing groups (PP5). Post_P 0.997 (odds of pathogenicity 3155, Prior_P 0.1). (less)
Pathogenic (Feb 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Anemia, nonspherocytic hemolytic, due to G6PD deficiency (X-linked recessive inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004175317.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Publications: PubMed (2) PubMed: 8364584‚ 22165289 Comment: The G6PD c.487G>A variant is classified as Pathogenic (PS3_Moderate, PS4, PM1, PM5, PP3) The G6PD c.487G>A variant is located in a splice region. The G6PD … (more) The G6PD c.487G>A variant is classified as Pathogenic (PS3_Moderate, PS4, PM1, PM5, PP3) The G6PD c.487G>A variant is located in a splice region. The G6PD c.487G>A variant is a single nucleotide change in exon 6/13 of the G6PD gene, which is predicted to change the amino acid glycine at position 163 in the protein to serine. The variant is commonly reported in patients with a clinical presentation of Glucose-6-phosphate dehydrogenase deficiency and haemolytic anaemia (HGMD:CM890050) (PS4). A molecular modelling of G6PD(p.Gly163Ser) was performed based on the X-ray structure of human G6PD. It is suggested that Ser-163 might affect the stability of G6PD alpha-helix d and beta-strand E, besides the conformation of beta-strand D. In conclusion, the biochemical and structural properties of G6PD(p.Gly163Ser) and G6PD(WT) enzymes are significantly different, which may be responsible for clinical diversity of G6PD deficiencies. (Lu et al, 2011; PMID: 22165289) (PS3_moderate). This variant is located in the conserved binding domain of the G6PD protein (PM1). This variant is a missense change at an amino acid residue where the different missense change p.Gly163Asphas been seen before (PMID:8364584) (PM5). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs137852314) and in the HGMD database: CM890050. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 10367). (less)
Pathogenic (Oct 30, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Anemia, nonspherocytic hemolytic, due to G6PD deficiency Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002023785.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
other (May 24, 2017)	no assertion criteria provided Method: literature only	G6PD MAHIDOL Affected status: not provided Allele origin: germline	OMIM Accession: SCV000031312.3 First in ClinVar: Apr 04, 2013 Last updated: May 27, 2017	Publications: PubMed (7) PubMed: 4435794‚ 1924316‚ 8956035‚ 1562739‚ 15349799‚ 11499668‚ 20007901 Comment on evidence: See Panich et al. (1972). A G-to-A change at base 487 (exon 6) leads to substitution of serine for glycine at amino acid 163 (Vulliamy, … (more) See Panich et al. (1972). A G-to-A change at base 487 (exon 6) leads to substitution of serine for glycine at amino acid 163 (Vulliamy, 1989). This mutation is polymorphic in Southeast Asia, causes class 2 enzyme derangement, and is associated with a new AluI site (Vulliamy et al., 1989). The same mutation was identified by Tang et al. (1992) in a Taiwanese in Taiwan. Matsuoka et al. (2004) found that 11% of blood samples from persons in remote areas of Myanmar (former Burma) indicated G6PD deficiency. Taken together with data from a previous report (Iwai et al., 2001), these findings indicated that 91.3% of G6PD variants were G6PD Mahidol. The findings suggested that the Myanmar population is derived from homogeneous ancestries different from those of Thai, Malaysian, and Indonesian populations. Louicharoen et al. (2009) investigated the effect of the G6PD-Mahidol 487A variant on human survival related to P. vivax and P. falciparum malaria in Southeast Asia. They showed that strong and recent positive selection has targeted the Mahidol variant over the past 1,500 years. The authors found that the G6PD-Mahidol variant reduces vivax, but not falciparum, parasite density in humans, which indicates that P. vivax has been a driving force behind the strong selective advantage conferred by this mutation. (less)
Likely pathogenic (Apr 18, 2021)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: unknown	Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare Accession: SCV004174916.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024	Clinical Features: delayed speech and language development (present) , autism (present) , behavioral abnormality (present) Age: 0-9 years Sex: male Ethnicity/Population group: South East Asian Geographic origin: Bangladesh
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Comment:

The hemizygous p.Gly193Ser variant in G6PD was identified by our study in one individual with non-spherocytic hemolytic anemia due to G6PD deficiency. This variant has been identified in 0.03657% (7/19142) of South Asian chromosomes, including 3 hemizygous individuals, and 0.01442% (2/13869) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137852314). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Although this variant has been seen in the general population, most individuals with non-spherocytic hemolytic anemia due to G6PD deficiency are asymptomatic. This variant has been reported pathogenic in ClinVar (Variation ID: 10367). The p.Gly193Ser variant in G6PD has been reported in 75 Southeast Asian individuals with G6PD Deficiency in the literature (PMID: 27880809, 2503817, 11499668, 15349799). The prevalence of this variant in affected individuals is significantly increased compared to the prevalence in large population studies, supporting pathogenicity. In vitro functional studies provide some evidence that the p.Gly193Ser variant may impact protein stability, activity, (PMID: 17959407, 8118045). In summary, the p.Gly193Ser variant is pathogenic. ACMG/AMP Criteria applied: PP3, PS3, PS4 (Richards 2015).

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 163 of the G6PD protein (p.Gly163Ser). This variant is present in population databases (rs137852314, gnomAD 0.04%). This missense change has been observed in individuals with glucose-6-phosphate dehydrogenase deficiency (PMID: 2503817, 11499668, 11793482, 21989994, 23926329, 26226515, 27880809). It is commonly reported in individuals of South Asian ancestry (PMID: 2503817, 11499668, 11793482, 21989994, 23926329, 26226515, 27880809). This variant is also known as G6PD Mahidol. ClinVar contains an entry for this variant (Variation ID: 10367). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects G6PD function (PMID: 8118045, 17959407, 22165289). For these reasons, this variant has been classified as Pathogenic.

Comment:

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 anemia (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 glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.001 for a recessive condition (5 heterozygotes, 3 hemizygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated NAD binding domain (Pfam). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternative missense change to aspartic acid has been described in individuals with severe G6PD deficiency (WHO class I; PMID: 27880809). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is one of the most common pathogenic G6PD variants in Thai and Burmese populations (WHO class II or III; ClinVar, PMID: 22171972, PMID: 25536053) (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant results in impaired folding and reduced protein stability (PMID: 17959407). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

Published functional studies demonstrate G163S is less stable than wild type in both thermostability and urea-induced inactivation tests, and is also impaired in its folding properties (PMID: 17959407); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20007901, 22165289, 29548282, 33069889, 34272389, 31323480, 11793482, 12215013, 36212142, 34659341, 33637102, 21989994, 27880809, 2503817, 29240263, 28356147, 28138089, 11499668, 1924316, 8956035, 15349799, 4435794, 1562739, 31589614, 34953813, 30097005, 29251006, 28376293, 17959407)

Comment:

The observed missense c.487G>A(p.Gly163Ser) variant in G6PD gene has been reported previously in multiple individuals affected with glucose-6-phosphate dehydrogenase deficiency (Sarker SK, et al., 2016; Li Q, et al., 2015; Nuchprayoon I, et al., 2002). Published functional studies demonstrate that this variant is less stable than wild type in both thermostability and urea-induced inactivation tests, and is also impaired in its folding properties (Huang Y, et al., 2008). The p.Gly163Ser variant has been reported with allele frequency of 0.004% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). Computational evidences (Polyphen - Probably damaging, SIFT - Tolerated and MutationTaster - Disease causing) predict conflicting evidence on protein structure and function for this variant. The amino acid change p.Gly163Ser in G6PD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 163 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.

Comment:

This variant in exon 6 of the G6PD gene results in the amino acid substitution from Glycine to Serine at codon 193 (p.Gly193Ser) with the sequence change of c.577G>A (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. The observed variant has a minor allele frequency of 0.00004400% 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 II variant associated with moderate G6PD deficiency (<10% activity), with intermittent hemolysis. The G6PD c.577G>A; p.Gly193Ser variant, also referred to as c.487G>A; p.Gly163Ser. This variant has previously been reported for Glucose-6- phosphate dehydrogenase (G6PD) deficiency by (Sarker SK et al., 2016 PMID: 27880809; Li Q et al., 2015 PMID: 26226515; Narang A et al., 2020 PMID: 32906206.)

Comment:

Variant summary: G6PD c.577G>A (p.Gly193Ser) results in a non-conservative amino acid change located in the Glucose-6-phosphate dehydrogenase, NAD-binding domain (IPR022674) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 181825 control chromosomes. c.577G>A, also known as G6PD Mahidol has been widely reported in the literature in multiple individuals affected with Glucose 6 Phosphate Dehydrogenase Deficiency and is considered among one of the most frequent mutations described among individuals of Vietnamese ancestry (example, Bancone_2019). These data indicate that the variant is very likely to be associated with disease. Mahidol variant has been shown to cause low or very low enzymatic activity in RBCs and is associated with relatively high hemolytic risk by 8-aminoquinolines treatment (cited in Bancone_2019). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

Variant found in unrelated hemizygotes with deficiency, some with jaundice, favism, and anemia (PS4_M, PP4). Decreased activity in red blood cells (0-30%) (PS3). Predicted to be damaging by SIFT and PolyPhen (PP3). Below expected carrier frequency in gnomAD (PM2). Reported as pathogenic by multiple clinical testing groups (PP5). Post_P 0.997 (odds of pathogenicity 3155, Prior_P 0.1).

Comment:

The G6PD c.487G>A variant is classified as Pathogenic (PS3_Moderate, PS4, PM1, PM5, PP3) The G6PD c.487G>A variant is located in a splice region. The G6PD c.487G>A variant is a single nucleotide change in exon 6/13 of the G6PD gene, which is predicted to change the amino acid glycine at position 163 in the protein to serine. The variant is commonly reported in patients with a clinical presentation of Glucose-6-phosphate dehydrogenase deficiency and haemolytic anaemia (HGMD:CM890050) (PS4). A molecular modelling of G6PD(p.Gly163Ser) was performed based on the X-ray structure of human G6PD. It is suggested that Ser-163 might affect the stability of G6PD alpha-helix d and beta-strand E, besides the conformation of beta-strand D. In conclusion, the biochemical and structural properties of G6PD(p.Gly163Ser) and G6PD(WT) enzymes are significantly different, which may be responsible for clinical diversity of G6PD deficiencies. (Lu et al, 2011; PMID: 22165289) (PS3_moderate). This variant is located in the conserved binding domain of the G6PD protein (PM1). This variant is a missense change at an amino acid residue where the different missense change p.Gly163Asphas been seen before (PMID:8364584) (PM5). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs137852314) and in the HGMD database: CM890050. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 10367).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Cut-off values for diagnosis of G6PD deficiency by flow cytometry in Thai population.	Thedsawad A	Annals of hematology	2022	PMID: 35840819
Molecular Characterization of G6PD Deficiency: Report of Three Novel G6PD Variants.	Arunachalam AK	Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion	2020	PMID: 32425388
Genotyping of Malaysian G6PD-deficient neonates by reverse dot blot flow-through hybridisation.	Alina MF	Journal of human genetics	2020	PMID: 31863082
Chinese newborn screening for the incidence of G6PD deficiency and variant of G6PD gene from 2013 to 2017.	Liu Z	Human mutation	2020	PMID: 31489982
Molecular characterization and mapping of glucose-6-phosphate dehydrogenase (G6PD) mutations in the Greater Mekong Subregion.	Bancone G	Malaria journal	2019	PMID: 30674319
Mutation of glucose-6-phosphate dehydrogenase deficiency in Chinese Han children in eastern Fujian.	Chen Y	Medicine	2018	PMID: 30045279
Molecular Analysis of Glucose-6-Phosphate Dehydrogenase Gene Mutations in Bangladeshi Individuals.	Sarker SK	PloS one	2016	PMID: 27880809
Prevalence and Molecular Characterization of Glucose-6-Phosphate Dehydrogenase Deficiency at the China-Myanmar Border.	Li Q	PloS one	2015	PMID: 26226515
Field trial evaluation of the performances of point-of-care tests for screening G6PD deficiency in Cambodia.	Roca-Feltrer A	PloS one	2014	PMID: 25541721
Characterization of G6PD genotypes and phenotypes on the northwestern Thailand-Myanmar border.	Bancone G	PloS one	2014	PMID: 25536053
Evaluation of the phenotypic test and genetic analysis in the detection of glucose-6-phosphate dehydrogenase deficiency.	Nantakomol D	Malaria journal	2013	PMID: 23965028
A randomized comparison of dihydroartemisinin-piperaquine and artesunate-amodiaquine combined with primaquine for radical treatment of vivax malaria in Sumatera, Indonesia.	Pasaribu AP	The Journal of infectious diseases	2013	PMID: 23926329
Glucose-6-phosphate dehydrogenase qingzhen: identification of a novel splice mutation (IVS5-1 G>A).	Liu WL	Pediatric blood & cancer	2012	PMID: 21989994
Prevalence and distribution of glucose-6-phosphate dehydrogenase (G6PD) variants in Thai and Burmese populations in malaria endemic areas of Thailand.	Phompradit P	Malaria journal	2011	PMID: 22171972
Enzyme kinetics and molecular modeling studies of G6PD(Mahidol) associated with acute hemolytic anemia.	Lu HR	Indian journal of biochemistry & biophysics	2011	PMID: 22165289
Positively selected G6PD-Mahidol mutation reduces Plasmodium vivax density in Southeast Asians.	Louicharoen C	Science (New York, N.Y.)	2009	PMID: 20007901
Glucose-6-phosphate dehydrogenase mutations in Mon and Burmese of southern Myanmar.	Nuchprayoon I	Journal of human genetics	2008	PMID: 18046504
Purification and detailed study of two clinically different human glucose 6-phosphate dehydrogenase variants, G6PD(Plymouth) and G6PD(Mahidol): Evidence for defective protein folding as the basis of disease.	Huang Y	Molecular genetics and metabolism	2008	PMID: 17959407
Structure and function of glucose-6-phosphate dehydrogenase-deficient variants in Chinese population.	Jiang W	Human genetics	2006	PMID: 16607506
Glucose-6-phosphate dehydrogenase variants associated with favism in Thai children.	Laosombat V	International journal of hematology	2006	PMID: 16513531
Molecular heterogeneity of glucose-6-phosphate dehydrogenase (G6PD) variants in the south of Thailand and identification of a novel variant (G6PD Songklanagarind).	Laosombat V	Blood cells, molecules & diseases	2005	PMID: 15727905
Complete molecular characterisation of glucose-6-phosphate dehydrogenase (G6PD) deficiency in a group of Malaysian Chinese neonates.	Ainoon O	The Malaysian journal of pathology	2004	PMID: 16329560
Glucose-6-phosphate dehydrogenase (G6PD) mutations in Myanmar: G6PD Mahidol (487G>A) is the most common variant in the Myanmar population.	Matsuoka H	Journal of human genetics	2004	PMID: 15349799
Glucose-6-phosphate dehydrogenase (G6PD) variants in Malaysian Malays.	Ainoon O	Human mutation	2003	PMID: 12497642
Glucose-6-phosphate dehydrogenase (G6PD) mutations in Thailand: G6PD Viangchan (871G>A) is the most common deficiency variant in the Thai population.	Nuchprayoon I	Human mutation	2002	PMID: 11793482
Distribution of glucose-6-phosphate dehydrogenase mutations in Southeast Asia.	Iwai K	Human genetics	2001	PMID: 11499668
Independent origin of single and double mutations in the human glucose 6-phosphate dehydrogenase gene.	Vulliamy T	Human mutation	1996	PMID: 8956035
Expression and biochemical characterization of human glucose-6-phosphate dehydrogenase in Escherichia coli: a system to analyze normal and mutant enzymes.	Tang TK	Blood	1994	PMID: 8118045
Variants of glucose-6-phosphate dehydrogenase are due to missense mutations spread throughout the coding region of the gene.	Vulliamy T	Human mutation	1993	PMID: 8364584
Frequency of glucose-6-phosphate dehydrogenase (G6PD) mutations in Chinese, Filipinos, and Laotians from Hawaii.	Hsia YE	Human genetics	1993	PMID: 8244337
Diverse point mutations result in glucose-6-phosphate dehydrogenase (G6PD) polymorphism in Taiwan.	Tang TK	Blood	1992	PMID: 1562739
Polymorphic sites in the African population detected by sequence analysis of the glucose-6-phosphate dehydrogenase gene outline the evolution of the variants A and A-.	Vulliamy TJ	Proceedings of the National Academy of Sciences of the United States of America	1991	PMID: 1924316
G6PD mahidol, a common deficient variant in South East Asia is caused by a (163)glycine----serine mutation.	Vulliamy TJ	Nucleic acids research	1989	PMID: 2503817
G-6-PD variants in Laotians.	Panich V	Human heredity	1974	PMID: 4435794
Characterization of glucose-6-phosphate dehydrogenase in Thailand. The occurrence of 6 variants among 50 G-6-PD deficient Thai.	Panich V	Humangenetik	1973	PMID: 4721339
G-6-PD Mahidol. The most common glucose-6-phosphate dehydrogenase variant in Thailand.	Panich V	Journal of the Medical Association of Thailand = Chotmaihet thangphaet	1972	PMID: 5081671
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=G6PD	-	-	-	-
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Text-mined citations for rs137852314 ...

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Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000402.4(G6PD):c.577G>A (p.Gly193Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs137852314 ...