X-154532269-C-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_001360016.2(G6PD):c.1376G>C(p.Arg459Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000661 in 1,209,746 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000055 ( 0 hom. 4 hem. )

Consequence

G6PD
NM_001360016.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

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 Pathogenic. Variant got 12 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

PP5

Variant X-154532269-C-G is Pathogenic according to our data. Variant chrX-154532269-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 10422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154532269-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PD	NM_001360016.2 link	c.1376G>C	p.Arg459Pro	missense_variant	Exon 12 of 13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4 link	c.1466G>C	p.Arg489Pro	missense_variant	Exon 12 of 13		NP_000393.4	P11413-3
G6PD	NM_001042351.3 link	c.1376G>C	p.Arg459Pro	missense_variant	Exon 12 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.1376G>C	p.Arg459Pro	missense_variant	Exon 12 of 13	1	NM_001360016.2	ENSP00000377192.3		P11413-1

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

112037

Hom.:

Cov.:

AF XY:

0.00

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:

0.000279

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000110

AC:

AN:

181938

Hom.:

AF XY:

0.00

AC XY:

AN XY:

66812

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.000223

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1097709

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

363135

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000238

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000179

AC:

AN:

112037

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34197

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000279

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000189

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Pathogenic:4

Dec 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg459 amino acid residue in G6PD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1562739, 2263506, 6714986, 8537082, 10643148, 11499668, 17726510, 20203002, 21446359, 25541721, 25775246, 26823837). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) performed at Invitae indicates that this missense variant is expected to disrupt G6PD protein function. ClinVar contains an entry for this variant (Variation ID: 10422). This variant is also known as Cosenza variant. This missense change has been observed in individual(s) with G6PD deficiency (PMID: 8447319, 9299858, 23365477). This variant is present in population databases (rs72554665, gnomAD 0.001%). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 459 of the G6PD protein (p.Arg459Pro). -

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 favism and anemia (PS4_M, PP4). Decreased activity in red blood cells (1-14%) (PS3). Affects same amino acid as pathogenic 459R>L (ClinVar ID 100058) (PM5). Below expected carrier frequency in gnomAD (PM2). Reported as pathogenic by Eurofins (PP5). Post_P 0.999 (odds of pathogenicity 6568, Prior_P 0.1). -

Aug 20, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3. -

Jun 08, 2023

Intergen, Intergen Genetics and Rare Diseases Diagnosis Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malaria, susceptibility to

Pathogenic:1

Feb 05, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Aug 31, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

G6PD deficiency

Pathogenic:1

Apr 05, 2019

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Across a selection of available literature, the G6PD c.1376G>C (p.Arg459Pro) missense variant, also referred to as c.1466G>C (p.Arg489Pro) or the "Cosenza" variant, has been reported in at least 24 individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency (Calabro et al. 1993; Barisic et al. 2005; Moosazadeh et al. 2013; Javadi et al. 2015). The p.Arg459Pro variant has been identified in multiple ethnic populations from countries around the Mediterranean (including Italy and Iran) and is most prevalent in Croatia. This variant is associated with a severe form of G6PD enzyme deficiency (Calabro et al. 1993; Moosazadeh et al. 2013). Control data are not available for this variant, which is reported at a frequency of 0.000248 in the Other population of the Genome Aggregation Database but this is based on one allele in a region of good sequencing coverage so the variant is presumed to be rare in the general population. Functional assays demonstrate that the p.Arg459Pro variant results in reduced enzyme activity, between 2% and 9.5% of normal (Calabro et al. 1993; Barisic et al. 2005). Based on the collective evidence, the p.Arg489Pro 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. -

G6PD COSENZA

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

0.96

BayesDel_addAF

Pathogenic

0.61

BayesDel_noAF

Pathogenic

0.63

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.91

D;D;D;.

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.99

.;.;D;D

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.96

D;D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Uncertain

2.7

M;M;M;.

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-2.3

.;.;N;N

REVEL

Pathogenic

0.84

Sift

Benign

0.080

.;.;T;T

Sift4G

Benign

0.097

T;.;T;T

Polyphen

0.98

D;D;D;.

Vest4

0.86

MutPred

0.89

Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);.;

MVP

1.0

MPC

2.4

ClinPred

0.69

GERP RS

5.6

Varity_R

0.98

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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