rs1050828

chrX-154536002-C-T

• Frequency:
  • Genomes: 𝑓 0.033 (155 hom., 995 hem., cov: 23)
  • Exomes 𝑓: 0.0091 (59 hom. 390 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Conflicting interpretations of pathogenicity criteria provided, conflicting interpretations P:28 U:2 O:3
• Conservation: PhyloP100: 3.75

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001360016.2
• PP5: Variant X-154536002-C-T is Pathogenic according to our data. Variant chrX-154536002-C-T is described in ClinVar as [Conflicting_interpretations_of_pathogenicity]. Clinvar id is 37123. Status of the report is criteria_provided_conflicting_interpretations, 1 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=20, Likely_pathogenic=2, Uncertain_significance=1}. Variant chrX-154536002-C-T is described in Lovd as [Likely_pathogenic]. Variant chrX-154536002-C-T is described in Lovd as [Pathogenic]. Variant chrX-154536002-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.0068126023).. Strength limited to SUPPORTING due to the PP5.
• BA1: GnomAd highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PD	NM_001360016.2	c.202G>A	p.Val68Met	missense_variant	4/13	ENST00000393562.10
G6PD	NM_000402.4	c.292G>A	p.Val98Met	missense_variant	4/13
G6PD	NM_001042351.3	c.202G>A	p.Val68Met	missense_variant	4/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10	c.202G>A	p.Val68Met	missense_variant	4/13	1	NM_001360016.2	P4

Frequencies

GnomAD3 genomes AF: 0.0335 AC: 3748 AN: 112041 Hom.: 155 Cov.: 23 AF XY: 0.0291 AC XY: 995 AN XY: 34237

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000368

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.000207

Gnomad OTH AF: 0.0305

GnomAD3 exomes AF: 0.00906 AC: 1661 AN: 183313 Hom.: 59 AF XY: 0.00575 AC XY: 390 AN XY: 67811

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.00401

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000367

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000183

Gnomad OTH exome AF: 0.00221

GnomAD4 exome AF: 0.00368 AC: 4043 AN: 1098048 Hom.: 173 AF XY: 0.00295 AC XY: 1071 AN XY: 363416

Gnomad4 AFR exome AF: 0.131

Gnomad4 AMR exome AF: 0.00489

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000296

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000653

Gnomad4 OTH exome AF: 0.00703

Alfa AF: 0.00603 Hom.: 191

Bravo AF: 0.0384

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.117 AC: 449

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00997 AC: 1211

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting interpretations of pathogenicity

Submissions summary: Pathogenic:28Uncertain:2Other:3

Revision: criteria provided, conflicting interpretations

LINK:

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:13Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jun 28, 2016	The c.202G>A (p.Val68Met) missense variant is recognized as a disease-causing variant in the G6PD gene. Functional studies demonstrate reduced enzymatic activity of the G allele compared to WT. The prevalence of the variant in affected individuals (homozygous) is increased compared with the prevalence in controls and there is familial co-segregation with disease (Bwayo et al. 2013; Manjurano et al. 2012; Maiga et al. 2014; Shah et al. 2014; Pisani et al. 2012; Vulliamy et al. 1988; Odievre et al. 2011). Although the frequency of this variant in the African population within ExAC (http://exac.broadinstitute.org) is high it is consistent with observed and expected based on disease incidence (11.34%). Computational algorithms predict the variant has a damaging or deleterious effect. This variant is has been classified as pathogenic by multiple reputable clinical testing laboratories (Emory, Division of Human Genetics at Children’s Hospital of Philadelphia). In summary, this variant c.202G>A (p.Val68Met) meets our criteria for a Pathogenic classification. We have confirmed this finding in our laboratory using Sanger sequencing. -
not provided, no assertion provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 10-30-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Aug 25, 2019	- -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Feb 20, 2015	This heterozygous variant (c.202G>A; p.Val68Met) has been reported under the name of “Asahi variant” when no other variants are present on the same haplotype; the enzymatic activity was reduced to 41% of wild type. This variant have been previously published as part of the same haplotype (A- variant) which results in reduced enzymatic activity to 10-23% of normal activity. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 12, 2022	This variant was identifiedas hemizygous and togehter with NM_001042351.3:c.376A>G._x000D_ Criteria applied: PS4, PS3_SUP, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 26, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Dec 02, 2022	ACMG classification criteria: PS3 supporting, PS4 strong, PP3 supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Nov 02, 2021	- -
Pathogenic, criteria provided, single submitter	curation	Dunham Lab, University of Washington	Aug 12, 2022	Variant found in three unrelated families, where hemizygotes present with deficiency, some with hyperbilirubinemia, jaundice, and anemia (PS4_M, PP4). Two son-and-mother pairs both have variant and decreased activity, and sons have additional symptoms (PP1). Decreased activity in red blood cells (3-71%) and when expressed in E. coli (PS3). Predicted to be damaging by SIFT and probably damaging by PolyPhen (PP3). Reported as pathogenic by multiple clinical testing groups (PP5). Post_P 0.994 (odds of pathogenicity 1516, Prior_P 0.1). -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 20, 2018	This sequence change replaces valine with methionine at codon 68 of the G6PD protein (p.Val68Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs1050828, ExAC 11%). ClinVar contains an entry for this variant (Variation ID: 37123).  This variant is also known as the Asashi variant or p.Val98Met in the literature. This variant frequently co-occurs with the c.376A>G (p.Asn126Asp) variant (rs1050829) in cis (on the same chromosome), which is known as the G6PD A- haplotype c.[202G>A; 376A>G] . The G6PD A- haplotype is the most prevalent G6PD deficiency variant in African populations which is present at 0.2% (PMID: 1303173, 24505519, 2572288, 4359638). ClinVar contains an entry for the G6PD A- haplotype (Variation ID: 10361). This variant has been reported to co-occur with another G6PD variant independent of the A- haplotype in a Japanese family affected with G6PD deficiency (PMID: 11852882). It has also been identified as homozygous independent of the A- haplotype in individuals suspected with G6PD deficiency (PMID: 23006493). While this variant alone has been shown to only mildly affect enzyme activity, the c.[202G>A; 376A>G] changes of the G6PD A- haplotype have been reported to act synergistically to cause dramatic reduction of the stability and enzymatic activity of the G6PD protein (PMID: 3393536, 1303173, 10734064, 6015571, 2836867, 16356170). For these reasons, this variant on the c.[202G>A; 376A>G] haplotype has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 15, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	Apr 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 27, 2016	The p.Val98Met variant in G6PD (frequently reported as p.Val68Met on transcript NM_001042351.1) is a well-established pathogenic variant for G6PD deficiency and has been shown to alter G6PD enzyme activity (Hirono 2002, Shah 2014). This var iant has also been identified in 11% (955/8415) of African chromosomes by the Ex ome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs105082 8). The variant's high frequency is consistent with the prevalence of G6PD defic iency in African populations and is thought to be a result of a partial protecti on against malaria (Manjurano 2012). The p.Val98Met variant is most frequently f ound in association with the common p.Asn156Asp allele. This combination indicat es the G6PD A- allele, which is a class III variant with a moderate level of def iciency (10-60% activity). In summary, the p.Val98Met meets criteria to be class ified as pathogenic for G6PD deficiency in an X-linked manner. -

not provided Pathogenic:10Uncertain:1

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	Criteria applied: PP1:Strong, PM1, PS4:Moderate, PP4, PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jul 02, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Jun 23, 2022	PS4, PP3, PP2, PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 04, 2022	PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2022	Results in 10-23% of normal G6PD activity and causes acute hemolytic anemia triggered by infections, certain drugs, and fava beans (Vulliamy et al., 1988; Beutler et al., 1989; Shah et al., 2014); This variant is associated with the following publications: (PMID: 12524354, 24943486, 21153663, 1889820, 22307442, 21931771, 8733135, 25182376, 23144702, 2836867, 11852882, 21479984, 25201310, 27884173, 2572288, 27853304, 28512736, 30609409, 31564435, 32387609, 1303173, 30577886, 31980526, 32641076, 33587123, 3393536, 34272389, 33069889, 33072997) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 24, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 02, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 29, 2017	- -

G6PD deficiency Pathogenic:2Other:1

not provided, no assertion provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 13, 2023	Variant summary: G6PD c.292G>A (p.Val98Met) results in a conservative amino acid change located in the NAD-binding domain (IPR022674) of 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 0.0091 in 183313 control chromosomes, predominantly at a frequency of 0.12 within the African or African-American subpopulation in the gnomAD database, including 59 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in G6PD causing Glucose 6 Phosphate Dehydrogenase Deficiency (0.0091 vs 0.29), and is consistent with the prevalence of G6PD deficiency in this region. Therefore, this allows no strong conclusion about variant significance. This variant is commonly observed as a complex variant (referred to as the A- haplotype) in cis with c.466A>G, p.Asn156Asp in individuals with Glucose 6 Phosphate Dehydrogenase Deficiency (e.g. Dallol_2012, Shah_2014). c.292G>A has also been reported as a single variant, independent from the A- haplotype, in the literature in the hemizygous, homozygous, and heterozygous state in multiple individuals affected with Glucose 6 Phosphate Dehydrogenase Deficiency, including at least two unrelated cases of an affected hemizygous male with an affected heterozygous mother (e.g. Hirono_2002, Dallol_2012, Warang_2017, Powers_2018, Chen_2018). These data indicate that the variant is very likely to be associated with disease. Publications have reported experimental evidence evaluating an impact on protein function (e.g. Town_1992, Shah_2014). The most pronounced variant effect results in an approximately 40% reduction in enzyme activity for heterozygotes, and 80% for hemizygotes and homozygotes. Furthermore, this variant has been given a WHO classification of Class III: mild to moderate enzyme deficiency (10-60% residual activity). Twenty-three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. The majority have classified the variant as pathogenic (n=19)/likely pathogenic (n=2), and two classified it as VUS. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 11, 2021	The G6PD c.292G>A (p.Val98Met) variant, which is also called c.202G>A (p.Val68Met), is a missense variant that has a well-characterized role in glucose-6-phosphate dehydrogenase (G6PD) deficiency, accounting for up to 25% of cases in sub-Saharan Africa. This variant has been reported in a large number of individuals with G6PD deficiency, including in a heterozygous, hemizygous, and homozygous state (Vulliamy et al. 1991; McDade et al. 2008; Tine et al. 2012; Dallol et al. 2012; Shah et al. 2014). It is commonly found in cis with the c.466A>G (p.Asn156Asp) variant, which is also known as c.376A>G (p.Asn126Asp), and this complex allele is often referred to as the A-(1) allele. The p.Val98Met variant is reported at a frequency of 0.116400 in the African/African American population of the Genome Aggregation Database (version 2.1.1), including in 90 homozygotes and 641 hemizygotes. This frequency is high but consistent with the prevalence of G6PD deficiency in this region and the potentially limited clinical expression of G6PD deficiency. Reduced enzyme activity of approximately 40% for heterozygotes and 80% for hemizygotes and homozygotes in red blood cells from individuals who carry the p.Val98Met variant only has been observed (Hirono et al. 2002; Shah et al. 2014). Based on the collective evidence, the p.Val98Met variant, is classified as pathogenic for G6PD deficiency. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 02, 2018

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 12, 2020

The c.[202G>A;376A>G] (p.[V68M;N126D]) complex allele affects exon 4 (coding exon 3) and exon 5 (coding exon 4) of the G6PD gene. This alteration results from a G to A substitution at nucleotide position 202, causing the valine (V) at amino acid position 68 to be replaced by a methionine (M), and from an A to G substitution at nucleotide position 376, causing the asparagine (N) at amino acid position 126 to be replaced by an aspartic acid (D). Based on data from the Genome Aggregation Database (gnomAD), the G6PD c.202G>A alteration was observed in 1.1% (2365/205030) total alleles studied, with a frequency of 11.6% (2208/18968) African alleles, including 89 homozygotes and 599 hemizygotes; the G6PD c.376A>G alteration was observed in 3.2% (6586/205081) total alleles studied, with a frequency of 31.8% (6025/18923) African alleles, including 714 homozygotes and 1605 hemizygotes. The G6PD c.[202G>A;376A>G] complex allele is also known as the “A-haplotype” and it is the most common G6PD-deficiency disease-causing allele in African populations. Of note, the c.376A>G (p.N126D) alteration is considered a benign variant when seen in isolation (Town, 1992; Shahjahani, 2013). A significant reduction in enzyme stability and activity has been observed when the c.202G>A (p.V68M) and c.376A>G (p.N126D) variants are present in cis (on the same chromosome) (Vulliamy, 1998; Town, 1992; Gómez-Gallego, 2000). Based on the available evidence, this alteration is classified as pathogenic. -

Anemia, nonspherocytic hemolytic, due to G6PD deficiency;C2939465:G6PD deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

research

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

-

G6PD c.292G>A (p.V98M) and c.466A>G (p.N156D), often occur together in cis as part of a haplotype, referred to as the enzyme variant A- (PMID: 5448; 1303173). This variant is associated with glucose-6-phosphate dehydrogenase deficiency. -

X-linked parkinsonism-spasticity syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

curation

Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University

Dec 30, 2017

- -

G6PD ASAHI Other:1

other, no assertion criteria provided

literature only

OMIM

Oct 24, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Uncertain

0.057

T

BayesDel_noAF

Pathogenic

0.41

Cadd

Uncertain

24

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

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

FATHMM_MKL

Uncertain

0.88

D

MetaRNN

Benign

0.0068

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

MetaSVM

Benign

-0.96

T

MutationAssessor

Pathogenic

3.4

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

MutationTaster

Benign

2.7e-7

P;P;P;P

PrimateAI

Uncertain

0.67

T

Sift4G

Uncertain

0.016

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

Polyphen

1.0

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

Vest4

0.43

MVP

0.98

MPC

0.51

ClinPred

0.057

T

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.88

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Other links and lift over

dbSNP: rs1050828; hg19: chrX-153764217; COSMIC: COSV63703414; COSMIC: COSV63703414;