rs137852341

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_001360016.2(G6PD):c.392G>T(p.Gly131Val) variant causes a missense change. The variant allele was found at a frequency of 0.000019 in 1,210,297 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000017 ( 0 hom. 2 hem. )

Consequence

G6PD
NM_001360016.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 4.68

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 8 ACMG points.

PP5

Variant X-154535261-C-A is Pathogenic according to our data. Variant chrX-154535261-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154535261-C-A is described in Lovd as [Pathogenic]. Variant chrX-154535261-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PD	NM_001360016.2 link	c.392G>T	p.Gly131Val	missense_variant	Exon 5 of 13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4 link	c.482G>T	p.Gly161Val	missense_variant	Exon 5 of 13		NP_000393.4	P11413-3
G6PD	NM_001042351.3 link	c.392G>T	p.Gly131Val	missense_variant	Exon 5 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.392G>T	p.Gly131Val	missense_variant	Exon 5 of 13	1	NM_001360016.2	ENSP00000377192.3		P11413-1

Frequencies

GnomAD3 genomes

AF:

0.0000357

AC:

AN:

112094

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34286

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:

0.00112

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:

0.0000763

AC:

AN:

183370

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

67902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00101

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:

0.0000173

AC:

AN:

1098148

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

363506

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000563

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000357

AC:

AN:

112149

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34351

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00112

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Pathogenic:4

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 G6PD deficiency, some with anemia (PP4, PS4_M). Decreased activity in red blood cells of hemizygotes (0-49%) (PS3). Predicted to be deleterious by REVEL and probably damaging by PolyPhen (PP3). Below expected carrier frequency in gnomAD (PM2). Post_P 0.994 (odds of pathogenicity 1517, Prior_P 0.1). -

May 27, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 22, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 08, 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 valine, which is neutral and non-polar, at codon 131 of the G6PD protein (p.Gly131Val). This variant is present in population databases (rs137852341, gnomAD 0.1%), 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: 11243133, 11400791, 25775246). It is commonly reported in individuals of South East Asian ancestry (PMID: 11243133, 11400791, 25775246). This variant is also known as the Quing Yuan or Chinese-4 variant. ClinVar contains an entry for this variant (Variation ID: 10404). 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%. For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic:2

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4+PP4+PS3_Supporting -

Jul 24, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malaria, susceptibility to

Pathogenic:1

Mar 30, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

May 18, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The G6PD c.392G>T; p.Gly131Val variant (rs137852341), also known as Chinese-4, is described in the literature in several individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency (Chiu 1993, Peng 2015. Additionally, this variant displays only 20 percent enzymatic activity compared to the wildtype protein (Chiu 1993), and is considered a class III variant (Fu 2018). This variant is also reported in ClinVar (Variation ID: 10404), and is found in the East Asian population with an allele frequency of 0.10% (15/14841 alleles, including 3 hemizygotes) in the Genome Aggregation Database. The glycine residue is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.855). Based on available information, this variant is considered to be pathogenic. References: Chiu DT et al. Molecular characterization of glucose-6-phosphate dehydrogenase (G6PD) deficiency in patients of Chinese descent and identification of new base substitutions in the human G6PD gene. Blood. 1993 81(8):2150-4. PMID: 8471773. 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. PMID: 29339739. Peng Q et al. Large cohort screening of G6PD deficiency and the mutational spectrum in the Dongguan District in Southern China. PLoS One. 2015 10(3):e0120683. PMID: 25775246. -

G6PD QUING YUAN

Other:1

Apr 18, 2013

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

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.64

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.94

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

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

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

M_CAP

Pathogenic

0.42

MetaRNN

Uncertain

0.74

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

2.9

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

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-5.2

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

REVEL

Pathogenic

0.85

Sift

Benign

0.037

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

Sift4G

Uncertain

0.046

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

Polyphen

0.99

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

Vest4

0.72

MVP

0.99

MPC

0.80

ClinPred

0.50

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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