X-154533596-C-G

Position:

chrX-154533596-C-G

Variant summary

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

The NM_001360016.2(G6PD):c.844G>C(p.Asp282His) variant causes a missense change. The variant allele was found at a frequency of 0.000892 in 1,211,000 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 313 hemizygotes in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., 17 hem., cov: 24)

Exomes 𝑓: 0.00091 ( 0 hom. 296 hem. )

Consequence

G6PD
NM_001360016.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18O:2

Conservation

PhyloP100: 4.62

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:

G6PD (HGNC:):

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-154533596-C-G is Pathogenic according to our data. Variant chrX-154533596-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 10372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154533596-C-G is described in Lovd as [Pathogenic]. Variant chrX-154533596-C-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
G6PD	NM_001360016.2 linkuse as main transcript	c.844G>C	p.Asp282His	missense_variant	8/13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4 linkuse as main transcript	c.934G>C	p.Asp312His	missense_variant	8/13		NP_000393.4	P11413-3
G6PD	NM_001042351.3 linkuse as main transcript	c.844G>C	p.Asp282His	missense_variant	8/13		NP_001035810.1	P11413-1A0A384NL00

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10 linkuse as main transcript	c.844G>C	p.Asp282His	missense_variant	8/13	1	NM_001360016.2	ENSP00000377192.3		P11413-1

Frequencies

GnomAD3 genomes

AF:

0.000718

AC:

AN:

112741

Hom.:

Cov.:

AF XY:

0.000487

AC XY:

AN XY:

34879

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000840

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000361

Gnomad FIN

AF:

0.000794

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00116

Gnomad OTH

AF:

0.000655

GnomAD3 exomes

AF:

0.000704

AC:

129

AN:

183239

Hom.:

AF XY:

0.000738

AC XY:

AN XY:

67729

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.000255

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000734

Gnomad FIN exome

AF:

0.000875

Gnomad NFE exome

AF:

0.00113

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000910

AC:

999

AN:

1098206

Hom.:

Cov.:

AF XY:

0.000814

AC XY:

296

AN XY:

363574

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

Gnomad4 AMR exome

AF:

0.000511

Gnomad4 ASJ exome

AF:

0.000103

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000480

Gnomad4 FIN exome

AF:

0.000740

Gnomad4 NFE exome

AF:

0.00103

Gnomad4 OTH exome

AF:

0.00115

GnomAD4 genome

AF:

0.000718

AC:

AN:

112794

Hom.:

Cov.:

AF XY:

0.000487

AC XY:

AN XY:

34942

show subpopulations

Gnomad4 AFR

AF:

0.0000964

Gnomad4 AMR

AF:

0.000839

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000362

Gnomad4 FIN

AF:

0.000794

Gnomad4 NFE

AF:

0.00117

Gnomad4 OTH

AF:

0.000647

Alfa

AF:

0.000903

Hom.:

Bravo

AF:

0.000737

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00134

AC:

ExAC

AF:

0.000865

AC:

105

EpiCase

AF:

0.00224

EpiControl

AF:

0.00113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Pathogenic:7

Pathogenic, criteria provided, single submitter	curation	Dunham Lab, University of Washington	Aug 12, 2022	Variant found in unrelated hemizygotes with deficiency, some with anemia, favism, and jaundice (PS4_M, PP4). In one family, hemizygous brothers have deficiency and heterozygous mother has decreased G6PD activity (PP1). Decreased activity in red blood cells (3-45%) and when expressed in E. coli (PS3). Predicted to be damaging by SIFT, probably damaging by PolyPhen (PP3). Below expected carrier frequency in gnomAD (PM2). Reported as pathogenic by multiple clinical testing groups (PP5). Post_P 0.999 (odds of pathogenicity 6563, Prior_P 0.1). -
Pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Jun 20, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Courtagen Diagnostics Laboratory, Courtagen Life Sciences	Apr 10, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 16, 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 deficiency (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 aspartic acid to histidine. (I) 0251 - This variant is heterozygous. (I) 0310 - Variant is present in gnomAD (v2) >=0.001 and <0.01 for a dominant condition (89 heterozygotes, 0 homozygotes, 53 hemizygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated G6PD C-terminal domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is a well-known pathogenic allele also known as G6PD Seattle/Ferrara II/Modena/Athens-like (ClinVar, PMID: 11146567, 12064920, 25536053). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Enzyme activity in patient cells is reduced relative to wild type, and in vitro studies support abnormal protein function (PMID: 11146567, 12064920, 30096395). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	This variant in exon 8 of the G6PD gene results in the amino acid substitution from Aspartic acid to Histidine at codon 312 (p.Asp312His) with the sequence change of c.934G>C (NM_000402.4). This variant was observed in a proband with decreased level of G6PD enzyme (<3.8 U/dL) which was screened for advanced newborn screening with confirmatory genetic reflex testing at lifecell diagnostics. The observed variant has a minor allele frequency of 0.0007040% in gnomAD database. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT are damaging. This is a Class III: variant associated with mild to moderate G6PD deficiency (0.10-0.60 normal activity), with intermittent hemolysis. The G6PD c.934G>C; p.Asp312His variant also referred to as c.844G>C; p.Asp282His, commonly known as G6PD-Ferrara II or Lodi or Modena or Seattle in the literature. This variant has previously been reported for Glucose-6- phosphate dehydrogenase (G6PD) deficieny by (Cappellini MD et al., 1994, PMID: 7947250; Alfinito F et al., 1994, PMID: 7947239; Rudilla F et al., 2019, PMID: 31681265) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 282 of the G6PD protein (p.Asp282His). This variant is present in population databases (rs137852318, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with G6PD deficiency (PMID: 2912069, 5305539, 7806085, 7947239, 7947250, 8807321). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10372). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects G6PD function (PMID: 7806085, 7947239). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 21, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jun 19, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 23, 2022	Published functional studies demonstrate that this variant reduces enzyme activity to 20% of wild type enzyme, and is associated with a mild form of G6PD deficiency (De Vita et al., 1989); This variant is associated with the following publications: (PMID: 2912069, 26990548, 30096395, 31681265, 7806085, 7947250, 8807321, 5305539, 7947239, 5770172, 4974311, 9299858, 34426522, 28902532, 35725860) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 12, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 01, 2017	The G6PD c.844G>C; p.Asp282His variant (rs137852318), also known as G6PD Seattle/Ferrara II/Modena/Athens-like, has been reported in multiple individuals in the Mediterranean region with G6PD deficiency (Cappellini 1994, Cappellini 1995, De Vita 1989, Frigerio 1994, Lenzerini 1969, Rattazzi 1969). Functional characterization indicates enzymatic activity ranging from 15 to 25 percent of wildtype (Cappellini 1994, Cappellini 1995, De Vita 1989, Frigerio 1994, Lenzerini 1969, Rattazzi 1969), consistent with a class III variant (WHO working group 1989). The variant is listed as pathogenic in ClinVar (Variation ID: 10372), and observed in the general population databases at a frequency of 0.07% (143/200329 alleles, including 52 hemizygotes) in the Genome Aggregation Database. The aspartate at codon 282 is moderately conserved, and computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Based on the available information, this variant is classified as pathogenic. REFERENCES Cappellini M et al. Biochemical and molecular characterization of a new sporadic glucose-6-phosphate dehydrogenase variant described in Italy: G6PD Modena. Br J Haematol. 1994; 87(1):209-11. Cappellini M et al. Molecular characterisation of the glucose-6-phosphate dehydrogenase (G6PD) Ferrara II variant. Hum Genet. 1995; 95(4):440-2. De Vita G et al. Two point mutations are responsible for G6PD polymorphism in Sardinia. Am J Hum Genet. 1989; 44(2):233-40. Frigerio R et al. Molecular and biochemical data on some glucose-6-phosphate dehydrogenase variants from southern Sardinia. Haematologica. 1994; 79(4):319-21. Lenzerin L et al. Characterization of glucose-6-phosphate dehydrogenase variants. I. Occurrence of a G6PD Seattle-like variant in Sardinia and its interaction with the G6PD Mediterranean variant. Am J Hum Genet. 1969; 21(2):142-53. Rattazzi M et al. Characterization of glucose-6-phosphate dehydrogenase variants. II. G6PD Kephalonia, G6PD Attica, and G6PD Seattle-like" found in Greece. Am J Hum Genet. 1969; 21(2):154-67. WHO working group. Glucose-6-phosphate dehydrogenase deficiency. Bull World Health Organ. 1989; 67(6):601-11. " -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	G6PD: PS4, PM5, PP1:Moderate, PS3:Moderate -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Malaria, susceptibility to

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 26, 2024

- -

G6PD-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 10, 2024

The G6PD c.844G>C variant is predicted to result in the amino acid substitution p.Asp282His. This variant also described using legacy nomenclature as p.Asp312His, referred to as G6PD Seattle-like, has been reported in individuals with moderate glucose-6-phosphate dehydrogenase deficiency (see, for example, De Vita et al. 1989. PubMed ID: 2912069; Calabrò et al. 1993. PubMed ID: 8447319; Manco et al. 2023. PubMed ID: 36150187). In vitro experimental studies suggest this variant impacts protein function (Cappellini et al. 1995. PubMed ID: 7705842; Rodrigues et al. 2002. PubMed ID: 12064920; Cortés-Morales et al. 2018. PubMed ID: 30096395). An alternative nucleotide substitution affecting the same amino acid (p.Asp282Tyr) has also been reported in individuals with glucose-6-phosphate dehydrogenase deficiency (Kawamoto et al. 2006. PubMed ID: 16927025). This variant is reported in 0.11% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

G6PD deficiency

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 16, 2023

Variant summary: G6PD c.934G>C (p.Asp312His) results in a non-conservative amino acid change located in the C-terminal domain (IPR022675) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0007 in 183239 control chromosomes. This frequency is not higher than the estimated maximum expected for a pathogenic variant in G6PD causing Glucose 6 Phosphate Dehydrogenase Deficiency (0.29), allowing no conclusion about variant significance. The variant, c.934G>C (aka. c.844G>C (p.D282H), G6PD Seattle-like, Ferrara II, Modena, Athens-like and Lodi), has been reported in the literature in numerous individuals affected with Glucose 6 Phosphate Dehydrogenase Deficiency (e.g. DeVita_1989, Frigerio_1994, Alfinito_1994, diMontemuros_1997), including at least one case of an affected (hemizygous) male and heterozygous mother with decreased enzyme activity. These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, and demonstrated decreased enzyme activity in hemizygous samples (~20 % of normal) as well as in in vitro expression systems (e.g. DeVita_1989, Frigerio_1994, Cappellini_1994, Cortes-Morales_2018, Alfinito_1994). The following publications have been ascertained in the context of this evaluation (PMID: 7806085, 30096395, 2912069, 7947250, 7947239, 9299858). 12 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

G6PD SEATTLE-LIKE

Other:1

other, no assertion criteria provided

literature only

OMIM

May 24, 2017

- -

G6PD MODENA

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

0.38

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.69

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.96

D;D;D;.;D;.

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

.;.;D;D;D;D

M_CAP

Pathogenic

0.53

MetaRNN

Uncertain

0.52

D;D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.6

M;M;M;.;.;.

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-4.6

.;.;D;D;D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

.;.;D;D;D;D

Sift4G

Uncertain

0.0030

D;.;D;D;.;.

Polyphen

0.99

D;D;D;.;.;.

Vest4

0.74

MVP

1.0

MPC

2.2

ClinPred

0.15

GERP RS

5.7

Varity_R

0.92

gMVP

0.97

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