NM_001360016.2:c.968T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 9P and 1B. PP3PP5_Very_StrongBP4

The NM_001360016.2(G6PD):​c.968T>C​(p.Leu323Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000254 in 1,211,131 control chromosomes in the GnomAD database, including 1 homozygotes. There are 79 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 0.0015 ( 1 hom., 46 hem., cov: 25)
Exomes 𝑓: 0.00013 ( 0 hom. 33 hem. )

Consequence

G6PD
NM_001360016.2 missense

Scores

9
3
5

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16U:1

Conservation

PhyloP100: 3.80
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PP3
Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_addAF, BayesDel_noAF, M_CAP, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
PP5
Variant X-154533025-A-G is Pathogenic according to our data. Variant chrX-154533025-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154533025-A-G is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.01999113). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
G6PDNM_001360016.2 linkc.968T>C p.Leu323Pro missense_variant Exon 9 of 13 ENST00000393562.10 NP_001346945.1
G6PDNM_000402.4 linkc.1058T>C p.Leu353Pro missense_variant Exon 9 of 13 NP_000393.4 P11413-3
G6PDNM_001042351.3 linkc.968T>C p.Leu323Pro missense_variant Exon 9 of 13 NP_001035810.1 P11413-1A0A384NL00

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
G6PDENST00000393562.10 linkc.968T>C p.Leu323Pro missense_variant Exon 9 of 13 1 NM_001360016.2 ENSP00000377192.3 P11413-1

Frequencies

GnomAD3 genomes
AF:
0.00150
AC:
170
AN:
112973
Hom.:
1
Cov.:
25
AF XY:
0.00131
AC XY:
46
AN XY:
35119
show subpopulations
Gnomad AFR
AF:
0.00456
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00212
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:
0.00329
GnomAD3 exomes
AF:
0.000530
AC:
97
AN:
183074
Hom.:
1
AF XY:
0.000355
AC XY:
24
AN XY:
67648
show subpopulations
Gnomad AFR exome
AF:
0.00563
Gnomad AMR exome
AF:
0.000766
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:
0.00
Gnomad OTH exome
AF:
0.000442
GnomAD4 exome
AF:
0.000126
AC:
138
AN:
1098104
Hom.:
0
Cov.:
33
AF XY:
0.0000908
AC XY:
33
AN XY:
363514
show subpopulations
Gnomad4 AFR exome
AF:
0.00265
Gnomad4 AMR exome
AF:
0.000966
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:
0.00000119
Gnomad4 OTH exome
AF:
0.000716
GnomAD4 genome
AF:
0.00150
AC:
170
AN:
113027
Hom.:
1
Cov.:
25
AF XY:
0.00131
AC XY:
46
AN XY:
35183
show subpopulations
Gnomad4 AFR
AF:
0.00455
Gnomad4 AMR
AF:
0.00212
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:
0.00325
Alfa
AF:
0.000114
Hom.:
4
Bravo
AF:
0.00175
ESP6500AA
AF:
0.00548
AC:
21
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000593
AC:
72

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:16Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:5Uncertain:1
Sep 01, 2024
Dunham Lab, University of Washington
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation

Variant reported in hemizygote with G6PD deficiency, anemia, and jaundice (PP4). Heterozygous mother also reported to have decreased activity (PP1), and activity was decreased in red blood cells of hemizygote (51%) (PS3). Below expected carreier frequency in gnomAD (PM2). Predicted to be damaging by a consensus of tools (PP3). Reported as pathogenic by multiple clinical testing groups (PP5). Post_P 0.994 (odds of pathogenicity 1516.9, Prior_P 0.1). -

Apr 08, 2021
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.1058T>C (p.Leu353Pro) results in a non-conservative amino acid change located in the C-terminal domain (IPR022675) of the encoded protein sequence. This variant has also been reported in the literature as c.968T>C (p.Leu323Pro) in transcript NM_001042351, and has been referred to as G6PD-Nefza. 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 0.00053 in 183074 control chromosomes in the gnomAD database, including 1 homozygote. c.1058T>C has been reported in the literature in multiple individuals affected with G6PD Deficiency. In most of these individuals, the variant was found in cis with a second variant in G6PD, c.466A>G (p.Asn156Asp; also known as c.376A>G, p.Asn126Asp) (e.g. Beutler_1989, Xu_1995, Vulliamy_1996, Rodrigues_2002, DeAraujo_2006, Jalloh_2008, Benkerrou_2013, Dijgo_2019). This complex allele [c.466A>G, c.1058T>C] has been referred to as "G6PD Betica or "G6PD Betica-Selma" in the literature. Experimental evidence has reported a reduction in G6PD activity in cells expressing either [c.466A>G, c.1058T>C] or c.1058T>C in isolation. In the same study, c.1058T>C was also shown to significantly reduce affinity for substrates G6P and NADP+ (Ramirez-Nava_2017). At least one publication reports the c.1058T>C variant in isolation in an individual who was diagnosed with hemolytic anemia after ingestion of fava beans (Benmansour_2013). This patient had a family history of G6PD deficiency, and G6PD activity in his cells was assessed to be approximately 51% that of wild-type. Collectively, these findings indicate that c.1058T>C is very likely to be associated with disease. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as pathogenic/likely pathogenic (n=5) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Sep 24, 2021
Johns Hopkins Genomics, Johns Hopkins University
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

c.[376A>G;968T>C] is a complex allele containing two G6PD variants (rs76723693; rs1050829) that are located on the same chromosome (in cis). Each variant has an entry in ClinVar. c.968T>C is rare (<0.1%) in a large population dataset (gnomAD: 127/205036 total alleles, 0.06%, 1 homozygote, 32 hemizygotes), while c.376A>G is polymorphic (3.2%) in most ancestral populations. This complex allele, sometimes referred to as "G6PD Betica-Selma", has been identified in approximately 7% of individuals with G6PD deficiency. In vitro functional studies have shown a reduction in G6PD activity (less than 50% enzyme activity) in cells expressing either c.[376A>G;968T>C] or c.968T>C in isolation. At least one publication reports the c.968T>C variant in isolation in an individual who was affected with neonatal jaundice and hemolytic anemia after ingestion of fava beans. This person had a family history of G6PD deficiency, and G6PD activity in his cells was approximately 51% that of wild type, consistent with a Class III variant (10-60% enzyme activity). c.376A>G has not been identified in isolation in affected individuals, but may act synergistically with other G6PD variants. Based on the available evidence, we consider this complex allele, which combines c.376A>G and c.968T>C, to be likely pathogenic. -

Aug 30, 2018
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: clinical testing

This sequence change replaces leucine with proline at codon 323 of the G6PD protein (p.Leu323Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs76723693, ExAC 0.6%). The c.968T>C (p.Leu323Pro) variant and the c.376A>G (p.Asn126Asp) variant, when co-occurring in cis, is known as G6PD Betica or G6PD Selma c.[376A>G; 968T>C], which is a subtype of the G6PD A- haplotype (PMID: 18056001, 2572288, 25915902, 27413522). The c.[376A>G; 968T>C] G6PD A- haplotype is the most prevalent G6PD deficiency variant in the Gambian population at 7% (PMID: 24615128, 26738565, 28067620). This variant alone has been reported in an individual affected with neonatal jaundice and hemolytic anemia triggered by fava beans (favism) (PMID: 22963789). ClinVar contains an entry for this variant (Variation ID: 10388). While the c.968T>C (p.Leu323Pro) variant alone has been shown to only mildly affect enzyme activity, the c.[376A>G; 968T>C] changes of the G6PD A- haplotype have been reported to act synergistically to cause dramatic reduction of the enzymatic activity of the G6PD protein (PMID: 18177777, 2633878, 2572288, 28067620, 28195434). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

May 28, 2019
Mendelics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 15, 2023
Revvity Omics, Revvity
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:5
Feb 10, 2014
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 11, 2022
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 04, 2025
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Functional studies demonstrate that p.(L323P) is associated with significantly decreased G6PD activity, stability, and catalytic efficiency; a further decrease in activity is seen when p.(L323P) is co-expressed with p.(N126D) (PMID: 29072585); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26738565, 19782058, 22237549, 35685917, 34451395, 32387609, 32702756, 24615128, 21931771, 22009270, 11852882, 27941691, 27267757, 28195434, 25141282, 22963798, 18177777, 12367584, 2633878, 3393536, 2836867, 30206300, 31525211, 30204801, 30409136, 30508000, 30071859, 28067620, 31564435, 33072997, 30755392, 31589614, 36681081, 37432431, 36007526, 31539204, 28902532, 33887194, 7803800, 29072585, 22963789, 21929367, 35313643, 34844289, 35199448, 38258498, 38645242, 25071003, 17611006, 2572288, 23006493, 33637102) -

Apr 19, 2022
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

G6PD: PM2, PS3:Moderate, PP1, PS4:Supporting -

G6PD deficiency Pathogenic:3
Jan 11, 2019
Illumina Laboratory Services, Illumina
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The G6PD c.968T>C (p.Leu323Pro) variant is a missense variant. Benmansour et al. (2013) reported the variant in a heterozygous state in two individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency as well as in a hemizygous state in one individual with a measured residual enzyme activity of 51% of wildtype. The p.Leu323Pro variant is commonly referred to as G6PD Nefza. This variant is more commonly reported in cis with another variant, p.Asn126Asp, which is referred to as G6PD A-; this complex allele has been identified in 76/1039 (7%) of individuals with G6PD deficiency (Beutler et al. 1989; Hamel et al. 2002; Monteiro et al. 2014; Reading et al. 2017). The p.Leu323Pro variant is reported at a frequency of 0.009970 in the African population of the 1000 Genomes Project. Functional studies in E. coli demonstrated the p.Leu323Pro variant shows 50% residual activity compared to the wildtype enzyme and results in reduced substrate affinity and G6PD expression (Ramirez-Nava et al. 2017). Importantly, comprehensive studies of the p.Leu323Pro, p.Asn126Asp, and complex alleles suggested the p.Leu323Pro variant was the primary contributor to the alterations in catalytic activity and structural modifications observed for the complex allele. Based on the available evidence, the p.Leu323Pro variant is classified as likely pathogenic for glucose-6-phosphate dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Jun 01, 1988
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Jan 06, 2020
Reproductive Health Research and Development, BGI Genomics
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: curation

NM_001042351.1:c.968T>C in the G6PD gene has an allele frequency of 0.005 in African subpopulation in the gnomAD database. This variant is more commonly reported in cis with another variant, p.Asn126Asp, which is referred to as G6PD A-; this complex allele has been identified in 76/1039 (7%) of individuals with G6PD deficiency (PMID: 2572288; 12367584; 25141282; 28195434). Functional studies demonstrated the p.Leu323Pro has a major contribution to the loss of affinity for both substrates in the double mutant G6PD A- (PMID29072585). Pathogenic computational verdict because 9 pathogenic predictions from DANN, DEOGEN2, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS3; PS4; PP4; PP3; -

Malaria, susceptibility to;C2720289:Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:1
Jun 18, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Malaria, susceptibility to Pathogenic:1
Mar 18, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

G6PD-related disorder Pathogenic:1
Apr 09, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The G6PD c.968T>C variant is predicted to result in the amino acid substitution p.Leu323Pro. The c.968T>C variant, when present on the same allele as the c.376A>G variant is together also referred to as G6PD Betica and is causative for glucose-6-phosphate dehydrogenase deficiency (Manco et al. 2007. PubMed ID: 18056001; Moradkhani et al. 2012. PubMed ID: 22139979). This variant is reported in 0.54% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.64
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.67
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.98
D;D;D;.;D
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.84
.;.;T;T;T
M_CAP
Pathogenic
0.91
D
MetaRNN
Benign
0.020
T;T;T;T;T
MetaSVM
Pathogenic
0.84
D
MutationAssessor
Pathogenic
3.1
M;M;M;.;.
PrimateAI
Uncertain
0.62
T
PROVEAN
Pathogenic
-4.6
.;.;D;D;D
REVEL
Pathogenic
0.81
Sift
Benign
0.048
.;.;D;D;T
Sift4G
Benign
0.068
T;.;T;T;.
Polyphen
0.25
B;B;B;.;.
Vest4
0.88
MVP
1.0
MPC
1.7
ClinPred
0.11
T
GERP RS
5.6
Varity_R
0.97
gMVP
0.99

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.

Other links and lift over

dbSNP: rs76723693; hg19: chrX-153761240; API