rs137852314

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM5PP3_ModeratePP5_Very_Strong

The NM_001360016.2(G6PD):c.487G>A(p.Gly163Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000038 in 1,209,982 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 25 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G163D) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., 5 hem., cov: 23)

Exomes 𝑓: 0.000036 ( 0 hom. 20 hem. )

Consequence

G6PD
NM_001360016.2 missense, splice_region

Scores

Splicing: ADA: 0.9163

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20O:1

Conservation

PhyloP100: 7.18

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]

G6PD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.938

PP5

Variant X-154534495-C-T is Pathogenic according to our data. Variant chrX-154534495-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154534495-C-T is described in Lovd as [Pathogenic]. Variant chrX-154534495-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PD	NM_001360016.2 link	c.487G>A	p.Gly163Ser	missense_variant, splice_region_variant	Exon 6 of 13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4 link	c.577G>A	p.Gly193Ser	missense_variant, splice_region_variant	Exon 6 of 13		NP_000393.4	P11413-3
G6PD	NM_001042351.3 link	c.487G>A	p.Gly163Ser	missense_variant, splice_region_variant	Exon 6 of 13		NP_001035810.1	P11413-1A0A384NL00

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10 link	c.487G>A	p.Gly163Ser	missense_variant, splice_region_variant	Exon 6 of 13	1	NM_001360016.2	ENSP00000377192.3		P11413-1

Frequencies

GnomAD3 genomes

AF:

0.0000534

AC:

AN:

112400

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

AN XY:

34574

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000283

Gnomad SAS

AF:

0.00181

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000440

AC:

AN:

181825

Hom.:

AF XY:

0.0000449

AC XY:

AN XY:

66749

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.000367

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000364

AC:

AN:

1097582

Hom.:

Cov.:

AF XY:

0.0000551

AC XY:

AN XY:

363042

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000132

Gnomad4 SAS exome

AF:

0.000443

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000260

GnomAD4 genome

AF:

0.0000534

AC:

AN:

112400

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

AN XY:

34574

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000283

Gnomad4 SAS

AF:

0.00181

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Pathogenic:11

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 21, 2024

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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, 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). -

Feb 07, 2023

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Apr 21, 2017

Centogene AG - the Rare Disease Company

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2024

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_v1.3.5, 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 (v4) <0.001 for a recessive condition (21 heterozygotes, 25 hemizygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated NAD binding domain (DECIPHER). (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 -

Oct 30, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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). -

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 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.) -

May 04, 2022

Mendelics

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 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. -

not provided

Pathogenic:5

Apr 18, 2021

Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 02, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 03, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, 37967096, 36681081, 34953813, 30097005, 29251006, 28376293, 17959407) -

Dec 21, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The G6PD c.487G>A;p.Gly163Ser variant (also known as G6PD Mahidol) has been published in the medical literature in individuals with G6PD deficiency and is associated with a mild to moderate decrease in enzyme activity (Huang 2008, Louicharoen 2009, Matsuoka 2007). This variant is also reported in ClinVar (Variation ID: 10367). This variant is found in the South Asian population with an allele frequency of 0.04% (7/19077 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.935). Based on available information, this variant is considered to be pathogenic. References: Huang Y et al. 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. Mol Genet Metab. 2008 Jan;93(1):44-53. PMID: 17959407. Louicharoen C et al. Positively selected G6PD-Mahidol mutation reduces Plasmodium vivax density in Southeast Asians. Science. 2009 Dec 11;326(5959):1546-9. PMID: 20007901. Matsuoka H et al. Seven different glucose-6-phosphate dehydrogenase variants including a new variant distributed in Lam Dong Province in southern Vietnam. Acta Med Okayama. 2007 Aug;61(4):213-9. PMID: 17726510. -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

G6PD: PM1, PM2, PM5, PS3:Moderate, PS4:Moderate -

G6PD deficiency

Pathogenic:2

Sep 08, 2022

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.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. -

Sep 08, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in G6PD is predicted to replace glycine with serine at codon 163, p.(Gly163Ser). The glycine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the glucose-6-phosphate dehydrogenase NAD-binding domain. There is a small physicochemical difference between glycine and serine. The highest population minor allele frequency in the population database gnomAD v4.1 is 0.05% (29/56,904 alleles, 20 hemizygotes) in the South Asian population. This variant is known as Mahidol and is highly prevalent in Thailand and Myanmar. It is a WHO Class B variant for G6PD deficiency (formerly Class II/III) which have median G6PD activity <45% of normal activity in homozygotes/hemizygotes and solid evidence that they induce acute haemolytic anaemia (PMID: 35247950, 37415281). Hemizygous individuals with this variant displayed a mean G6PD activity of 15% of normal activity (PMID: 37415281). Heterozygous females with this variant had an increased risk of primaquine-induced haemolysis compared to controls (PMID: 28170391). Functional studies with limited validation assaying G6PD activity are supportive of a damaging effect on protein function (PMID: 22165289, 17959407). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.935) and predicts no impact on splicing (SpliceAI) for the nucleotide change. Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as PATHOGENIC, low penetrance. -

Malaria, susceptibility to;C2720289:Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malaria, susceptibility to

Pathogenic:1

Mar 20, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

G6PD MAHIDOL

Other:1

May 24, 2017

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

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.68

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;D;D;.;D;.;D

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

.;.;D;D;D;D;D

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.2

M;M;M;M;.;.;.

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-4.3

.;.;D;D;D;D;D

REVEL

Pathogenic

0.94

Sift

Benign

0.048

.;.;D;D;D;D;D

Sift4G

Uncertain

0.032

D;.;D;D;.;.;.

Polyphen

0.98

D;D;D;.;.;.;.

Vest4

0.87

MutPred

0.93

Loss of catalytic residue at I162 (P = 0.1428);Loss of catalytic residue at I162 (P = 0.1428);Loss of catalytic residue at I162 (P = 0.1428);Loss of catalytic residue at I162 (P = 0.1428);.;.;Loss of catalytic residue at I162 (P = 0.1428);

MVP

0.99

MPC

0.70

ClinPred

0.55

GERP RS

5.7

Varity_R

0.88

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.92

SpliceAI score (max)

0.040

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over