rs137852320

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PM2PP2PP3PP5_Very_Strong

The NM_001360016.2(G6PD):c.1156A>G(p.Lys386Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 25)

Consequence

G6PD
NM_001360016.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6O:4

Conservation

PhyloP100: 2.29

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

anemia, nonspherocytic hemolytic, due to G6PD deficiency
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
G6PD deficiency
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
class I glucose-6-phosphate dehydrogenase deficiency
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

G6PD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM1

In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001360016.2

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 185 curated pathogenic missense variants (we use a threshold of 10). The gene has 42 curated benign missense variants. Gene score misZ: 2.0008 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to anemia, nonspherocytic hemolytic, due to G6PD deficiency, class I glucose-6-phosphate dehydrogenase deficiency, G6PD deficiency.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.792

PP5

Variant X-154532698-T-C is Pathogenic according to our data. Variant chrX-154532698-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 10375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
G6PD	NM_001360016.2 link	c.1156A>G	p.Lys386Glu	missense_variant	Exon 10 of 13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4 link	c.1246A>G	p.Lys416Glu	missense_variant	Exon 10 of 13		NP_000393.4
G6PD	NM_001042351.3 link	c.1156A>G	p.Lys386Glu	missense_variant	Exon 10 of 13		NP_001035810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10 link	c.1156A>G	p.Lys386Glu	missense_variant	Exon 10 of 13	1	NM_001360016.2	ENSP00000377192.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.000265

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Other:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Pathogenic:3

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 386 of the G6PD protein (p.Lys386Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glucose-6-phosphate dehydrogenase deficiency (PMID: 2602358; internal data). This variant is also known as G-6-PD Walter Reed. ClinVar contains an entry for this variant (Variation ID: 10375). 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.

Jan 05, 2024

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

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 and CNSHA (PS4_M, PP4). In one family, hemizygote and heterozygous maternal grandmother have history of hemolytic anemia (PP1). Decreased activity in red blood cells (1-13%) (PS3). Within dimer interface (PM1). Not found in gnomAD (PM2). Reported as pathogenic by multiple clinical testing groups (PP5). Post_P 0.999 (odds of pathogenicity 13661, Prior_P 0.1).

not provided

Pathogenic:2

Apr 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The G6PD c.1156A>G; p.Lys386Glu variant (also known as G6PD Iowa, G6PD Iowa City, G6PD Springfield, G6PD Walter Reed) (rs137852320) is classified as a class I variant associated with severe G6PD enzyme deficiency and chronic non-spherocytic hemolytic anemia, and is reported in the literature in several affected individuals (Beutler 1986, Hirono 1989, Mason 1995, Vulliamy 1998). This variant is reported in ClinVar (Variation ID: 10375). This variant is also absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Functional analysis of the variant protein shows nearly abolished G6PD enzyme activity compared to wild type (Park 2005). Computational analyses predict that this variant is deleterious (REVEL: 0.701). Based on available information, this variant is considered to be pathogenic. References: Beutler E et al. G-6-PD Walter Reed: possible insight into "structural" NADP in G-6-PD. Am J Hematol. 1986 Sep;23(1):25-30. PMID: 3740052. Hirono A et al. Identification of the binding domain for NADP+ of human glucose-6-phosphate dehydrogenase by sequence analysis of mutants. Proc Natl Acad Sci U S A. 1989 Dec;86(24):10015-7. PMID: 2602358. Mason PJ et al. New glucose-6-phosphate dehydrogenase mutations associated with chronic anemia. Blood. 1995 Mar 1;85(5):1377-80. PMID: 7858267. Park J et al. Overexpression of glucose-6-phosphate dehydrogenase is associated with lipid dysregulation and insulin resistance in obesity. Mol Cell Biol. 2005 Jun;25(12):5146-57. PMID: 15923630. Vulliamy TJ et al. Clinical and haematological consequences of recurrent G6PD mutations and a single new mutation causing chronic nonspherocytic haemolytic anaemia. Br J Haematol. 1998 Jun;101(4):670-5. PMID: 9674740.

Jan 04, 2016

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

G6PD-related disorder

Pathogenic:1

Mar 13, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The G6PD c.1156A>G variant is predicted to result in the amino acid substitution p.Lys386Glu. This variant has been reported to be pathogenic for glucose-6-phosphate dehydrogenase deficiency likely due to altered lysine acetylation (Hirono et al. 1989. PubMed ID: 2602358; Suo et al. 2013. PubMed ID: 23298314). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.

G6PD WALTER REED

Other:1

May 24, 2017

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

G6PD IOWA CITY

Other:1

May 24, 2017

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

G6PD IOWA

Other:1

May 24, 2017

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

G6PD SPRINGFIELD

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

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.50

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;D;D;.

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.0

.;.;D;D

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.79

D;D;D;D

MetaSVM

Pathogenic

1.4

MutationAssessor

Benign

1.3

L;L;L;.

PhyloP100

2.3

PrimateAI

Uncertain

0.66

PROVEAN

Benign

0.0

.;.;D;D

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.;T;T

Sift4G

Benign

0.57

T;.;T;T

Vest4

0.46

ClinPred

0.72

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.84

gMVP

0.92

Mutation Taster

=15/85

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over