rs72554665

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4

The NM_001360016.2(G6PD):c.1376G>T(p.Arg459Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000133 in 1,209,798 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 44 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., 12 hem., cov: 23)

Exomes 𝑓: 0.00012 ( 0 hom. 32 hem. )

Consequence

G6PD
NM_001360016.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15O:4

Conservation

PhyloP100: 3.69

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 Likely_pathogenic. Variant got 7 ACMG points.

PP5

Variant X-154532269-C-A is Pathogenic according to our data. Variant chrX-154532269-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 100058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154532269-C-A is described in Lovd as [Pathogenic]. Variant chrX-154532269-C-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.014364898). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
G6PD	NM_001360016.2 linkuse as main transcript	c.1376G>T	p.Arg459Leu	missense_variant	12/13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4 linkuse as main transcript	c.1466G>T	p.Arg489Leu	missense_variant	12/13		NP_000393.4
G6PD	NM_001042351.3 linkuse as main transcript	c.1376G>T	p.Arg459Leu	missense_variant	12/13		NP_001035810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10 linkuse as main transcript	c.1376G>T	p.Arg459Leu	missense_variant	12/13	1	NM_001360016.2	ENSP00000377192	P4	P11413-1

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

112037

Hom.:

Cov.:

AF XY:

0.000351

AC XY:

AN XY:

34197

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:

0.00781

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000813

AC:

148

AN:

181938

Hom.:

AF XY:

0.000584

AC XY:

AN XY:

66812

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000366

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0107

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000121

AC:

133

AN:

1097708

Hom.:

Cov.:

AF XY:

0.0000881

AC XY:

AN XY:

363134

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00407

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000195

GnomAD4 genome

AF:

0.000250

AC:

AN:

112090

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

34260

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00784

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000276

ExAC

AF:

0.000577

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15Other:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 21, 2023	- -
Pathogenic, criteria provided, single submitter	curation	Dunham Lab, University of Washington	Aug 12, 2022	Variant found in unrelated hemizygotes with deficiency, some with anemia, jaundice, and kernicterus (PS4_M, PP4). Segregates with deficiency in multiple unrelated families (PP1). Decreased activity in red blood cells (1-52%) (PS3). Affects same amino acid as pathogenic 459R>P (ClinVar ID 10422) (PM5). Predicted to be disease causing by Mutation Taster and possibly damaging by PolyPhen (PP3). Below expected carrier frequency in gnomAD (PM2). Reported as pathogenic by multiple clinical testing groups (PP5). Post_P 0.9997 (odds of pathogenicity 28416, Prior_P 0.1). -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Dec 21, 2023	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 arginine to leucine. (I) 0253 - This variant is hemizygous. (I) 0305 - Variant is present in gnomAD >=0.01 and <0.03 for a recessive condition in the East Asian subpopulation (115 heterozygotes, 0 homozygotes, 43 hemizygotes). (I) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 1 heterozygote, 0 homozygotes, 1 hemizygote). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated glucose-6-phosphate dehydrogenase, C-terminal domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, is referred to as the Canton variant, and is enriched in East Asian populations (ClinVar, PMID: 36315991). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 06, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 459 of the G6PD protein (p.Arg459Leu). This variant is present in population databases (rs72554665, gnomAD 1.0%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with glucose-6-phosphate deficiency (PMID: 1562739, 2263506, 6714986, 8537082, 10643148, 11499668, 17726510, 20203002, 21446359, 25541721, 25775246, 26823837). It has also been observed to segregate with disease in related individuals. This variant is also known as Canton variant. ClinVar contains an entry for this variant (Variation ID: 100058). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on G6PD protein function. Experimental studies have shown that this missense change affects G6PD function (PMID: 16607506). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 02, 2021	The G6PD c.1376G>T; p.Arg459Leu variant (rs72554665) is reported in the literature in the hemizygous, homozygous, and compound heterozygous states in individuals of East Asian descent affected with G6PD deficiency (Fu 2018, Stevens 1990, Tang 1992). Individuals carrying this variant have been shown to have G6PD enzymatic activity lower than levels found in the general Chinese population (Tang 1992) and this variant has been reported in 27.5% of positive newborn screens for G6PD deficiency in Guangxi, China (Fu 2018). The variant is reported in ClinVar (Variation ID: 100058), and it is found in the East Asian population with an overall allele frequency of 1.1% (157/14796 alleles with 42 hemizygotes) in the Genome Aggregation Database. The arginine at codon 459 is moderately conserved and is located in the dehydrogenase domain. Additionally, another missense variant at the same amino acid (p.Arg459Pro) has been observed in individuals with G6PD deficiency and is considered pathogenic (Calabro 1993). Based on available information, the p.Arg459Leu variant is considered to be pathogenic. References: Calabro V et al. Genetic heterogeneity of glucose-6-phosphate dehydrogenase deficiency revealed by single-strand conformation and sequence analysis. Am J Hum Genet. 1993 Mar;52(3):527-36. Fu C et al. Newborn screening of glucose-6-phosphate dehydrogenase deficiency in Guangxi, China: determination of optimal cutoff value to identify heterozygous female neonates. Sci Rep. 2018 Jan 16;8(1):833. Stevens D et al. G6PD Canton a common deficient variant in South East Asia caused by a 459 Arg----Leu mutation. Nucleic Acids Res. 1990: 18(23):7190. Tang T et al. Diverse point mutations result in glucose-6-phosphate dehydrogenase (G6PD) polymorphism in Taiwan. Blood. 1992: 79(8):2135-40. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 20, 2022	PP4, PP5, PM5, PS3, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2023	In vitro functional studies indicate that R459L has a reduced catalytic efficiency of approximately 50% compared to wild type enzyme (Boonyuen et al., 2017); 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: 9891846, 34659341, 34746046, 2263506, 11499668, 14505231, 1953767, 29783823, 29339739, 11793482, 31374327, 34570182, 12215013, 34953813, 29251006, 35193651, 28376293, 35313968, 8571933, 28583873) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 09, 2015	- -

G6PD deficiency

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 05, 2019	The G6PD c.1376G>T (p.Arg459Leu) missense variant, also described as G6PD Canton, is one of the most common glucose-6-phosphate dehydrogenase (G6PD) deficiency variants in certain Asian populations. Across a selection of the available literature, the p.Arg459Leu variant was observed in 116 G6PD deficiency cases, mostly in individuals of Chinese ancestry (Stevens et al. 1990; Tang et al. 1992; Cai et al. 2000; Deng et al. 2007; Phompradit et al. 2011; Yang et al. 2014). Control data are unavailable for the p.Arg459Leu variant, which is reported at a frequency of 0.01061 in the East Asian population of the Genome Aggregation Database including 42 hemizygotes in this population and 43 hemizygotes in the total population. Based on the evidence, the p.Arg459Leu variant is classified as pathogenic for glucose-6-phosphate dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_001042351.1:c.1376G>T in the G6PD gene has an allele frequency of 0.012 in East Asian subpopulation in the gnomAD database. The c.1376G>T (p.Arg459Leu) variant was observed in numerous G6PD deficiency cases, mostly in individuals of Chinese ancestry (PMID: 25440321; 22171972; 21874587). Experimental studies have shown that this missense change causes a significant reduction in enzyme activity and affinity for glucose-6-phosphate (PMID: 16607506). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, FATHMM-MKL, MVP, MutationTaster and REVEL. ACMG/AMP Criteria applied: PS3; PS4; PP4; PP3. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 18, 2022

- -

Malaria, susceptibility to

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 28, 2024

- -

G6PD-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 27, 2024

The G6PD c.1376G>T variant is predicted to result in the amino acid substitution p.Arg459Leu. This variant, referred to as G6PD Canton, has previously been reported to causative for Glucose-6-Phosphate Dehydrogenase deficiency (Wang X et al 2021. PubMed ID: 34659341; Nuchprayoon I et al 2002. PubMed ID: 11793482; Stevens et al 1990. PubMed ID: 2263506; Yusoff NM et al 2002. PubMed ID: 12215013). This variant is interpreted as pathogenic. -

G6PD AGRIGENTO

Other:1

other, no assertion criteria provided

literature only

OMIM

May 24, 2017

- -

G6PD TAIWAN-HAKKA

Other:1

other, no assertion criteria provided

literature only

OMIM

May 24, 2017

- -

G6PD GIFU

Other:1

other, no assertion criteria provided

literature only

OMIM

May 24, 2017

- -

G6PD CANTON

Other:1

other, no assertion criteria provided

literature only

OMIM

May 24, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.59

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;D;D;.

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.99

.;.;D;D

MetaRNN

Benign

0.014

T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.7

L;L;L;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.8

.;.;D;D

REVEL

Pathogenic

0.70

Sift

Benign

0.12

.;.;T;T

Sift4G

Benign

0.14

T;.;T;T

Polyphen

0.73

P;P;P;.

Vest4

0.56

MVP

1.0

MPC

1.9

ClinPred

0.20

GERP RS

5.6

Varity_R

0.72

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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