rs5030872

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_001360016.2(G6PD):c.542A>T(p.Asp181Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000777 in 1,209,769 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., 7 hem., cov: 23)

Exomes 𝑓: 0.000041 ( 0 hom. 15 hem. )

Consequence

G6PD
NM_001360016.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 7.78

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-154534440-T-A is Pathogenic according to our data. Variant chrX-154534440-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 37203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154534440-T-A is described in Lovd as [Pathogenic]. Variant chrX-154534440-T-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.16829187). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PD	NM_001360016.2 link	c.542A>T	p.Asp181Val	missense_variant	Exon 6 of 13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4 link	c.632A>T	p.Asp211Val	missense_variant	Exon 6 of 13		NP_000393.4	P11413-3
G6PD	NM_001042351.3 link	c.542A>T	p.Asp181Val	missense_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.542A>T	p.Asp181Val	missense_variant	Exon 6 of 13	1	NM_001360016.2	ENSP00000377192.3		P11413-1

Frequencies

GnomAD3 genomes

AF:

0.000438

AC:

AN:

111781

Hom.:

Cov.:

AF XY:

0.000206

AC XY:

AN XY:

33999

show subpopulations

Gnomad AFR

AF:

0.00124

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00103

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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:

0.000136

AC:

AN:

183162

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

67684

show subpopulations

Gnomad AFR exome

AF:

0.00106

Gnomad AMR exome

AF:

0.000292

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:

0.0000245

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000410

AC:

AN:

1097988

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

363384

show subpopulations

Gnomad4 AFR exome

AF:

0.000871

Gnomad4 AMR exome

AF:

0.000313

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:

0.000174

GnomAD4 genome

AF:

0.000438

AC:

AN:

111781

Hom.:

Cov.:

AF XY:

0.000206

AC XY:

AN XY:

33999

show subpopulations

Gnomad4 AFR

AF:

0.00124

Gnomad4 AMR

AF:

0.00103

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000754

Hom.:

Bravo

AF:

0.000536

ESP6500AA

AF:

0.00130

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000140

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Aug 23, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Biochemical studies of G6PD enzyme activity from patient blood samples showed that G6PD Malaga (D181V) and G6PD Santamaria (D181V+N126D) have similar abnormal kinetic properties, though G6PD Santamaria showed additional abnormalities thought to be due to the interaction of both variants (PMID: 8956035); Published functional studies demonstrate that the G6PD Santamaria variant (D181V+N126D) causes lower levels of expression of soluble protein as well as reduced enzyme activity compared to both wild-type GP6D and G6PD harboring the N126D variant alone (PMID: 26633385); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27267757, 21931771, 26738565, 17611006, 10571945, 6433630, 1879833, 9233561, 8956035, 31589614, 36681081, 36007526, 34272389, 26633385, 33637102) -

Jun 14, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4 -

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

G6PD: PM2, PS4:Moderate, PP4, PS3:Supporting -

Nov 05, 2012

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 08, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Pathogenic:4

Dec 03, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Evidence in support of pathogenic classification: - Variant is present in gnomAD <0.01 (v4: 72 heterozygote(s), 0 homozygote(s), 22 hemizygote(s)) . - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant alone, known as the Malaga variant, as well as this variant in cis with c.376A>G; p.Asn126Asp, known as the Santa Maria haplotype, have both been reported in individuals with G6PD deficient haemolytic anaemia (ClinVar, PMID: 10571945, PMID: 22293322, PMID: 36681081). Additional information: - Variant is predicted to result in a missense amino acid change from aspartic acid to valine. - This variant is hemizygous. - 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. - Variant is located in the annotated Glucose-6-phosphate dehydrogenase, NAD binding domain (DECIPHER). - Missense variant with inconclusive in silico prediction and uninformative conservation. - Loss of function is a known mechanism of disease in this gene and is associated with G6PD deficient hemolytic anemia (favism) (MIM#300908). - Inheritance information for this variant is not currently available in this individual. -

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 181 of the G6PD protein (p.Asp181Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. The c.542A>T (p.Asp181Val) variant and the c.376A>G (p.Asn126Asp) variant, when co-occurring in cis as c.[376A>G;542A>T], is known as the G6PD Santa Maria haplotype. The c.542A>T (p.Asn181Val) variant alone (PMID: 10571945, 8956035) and the Santa Maria haplotype (PMID: 1879833, 22963789, 12367584, 8956035, 22906837) have both been observed in individuals affected with G6PD deficiency. ClinVar contains an entry for this variant (Variation ID: 37203). 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) has been performed 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 are not available for the c.542A>T (p.Asn181Val) variant alone, but in vitro studies have shown that the G6PD Santa Maria haplotype abrogates enzyme activity and reduces affinity for the substrate (PMID: 26633385). For these reasons, this variant has been classified as Pathogenic. -

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, favism, and anemia (PS4_M, PP4). Decreased activity in red blood cells (6%) (PS3). Below expected carrier frequency in gnomAD (PM2). Reported as pathogenic by multiple clinical testing groups (PP5). Not found in gnomAD (PM2). Post_P 0.994 (odds of pathogenicity 1517, Prior_P 0.1). -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malaria, susceptibility to

Pathogenic:1

Mar 08, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

G6PD deficiency

Pathogenic:1

Apr 19, 2024

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.632A>T (p.Asp211Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 183162 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in G6PD causing Glucose 6 Phosphate Dehydrogenase Deficiency (0.00014 vs 0.29), allowing no conclusion about variant significance. c.632A>T has been reported in the literature as c.542A>T (p.Asp181Val) or G6PD Malaga in isolation and as G6PD Santamaria association with c.376A>G (p. Asn126Asp, the nondeficient polymorphic variant G6PD A+ as stated in Al-Sweedan_2012) in multiple individuals affected with clinical manifestations of Favism and Glucose 6 Phosphate Dehydrogenase Deficiency (example, Vulliamy_1996, Al Sweedan_2012, Benmansour_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in isolation and as the G6PD Santamaria haplotype (Vulliamy_1996). The most pronounced variant effect in isolation (G6PD Malaga) results in a residual RBC activity of 6.4% of normal, a slower than normal electrophoretic mobility, a markedly decreased Km for both G6P and NADP, striking decreases in utilization rates of 2-deoxy G6P and deamino NADP, a normal thermostability and pH optimum curve. The following publications have been ascertained in the context of this evaluation (PMID: 22906837, 9233561, 22963789, 8956035). ClinVar contains an entry for this variant (Variation ID: 37203). Based on the evidence outlined above, the variant in isolation and in cis with c.376A>G as G6PD Santamaria was classified as pathogenic. -

G6PD MALAGA

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

Benign

0.18

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.34

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Pathogenic

0.81

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

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.17

T;T;T;T;T;T;T

MetaSVM

Uncertain

0.38

MutationAssessor

Benign

-0.29

N;N;N;N;.;.;.

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-2.4

.;.;N;N;N;N;N

REVEL

Uncertain

0.61

Sift

Benign

0.073

.;.;T;T;T;T;T

Sift4G

Benign

0.16

T;.;T;T;.;.;.

Polyphen

0.0080

B;B;B;.;.;.;.

Vest4

0.68

MVP

1.0

MPC

0.29

ClinPred

0.057

GERP RS

5.7

Varity_R

0.71

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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