X-154532676-C-T
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001360016.2(G6PD):c.1178G>A(p.Arg393His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 25)
Consequence
G6PD
NM_001360016.2 missense
NM_001360016.2 missense
Scores
14
2
1
Clinical Significance
Conservation
PhyloP100: 7.36
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
Variant X-154532676-C-T is Pathogenic according to our data. Variant chrX-154532676-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154532676-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| G6PD | NM_001360016.2 | c.1178G>A | p.Arg393His | missense_variant | Exon 10 of 13 | ENST00000393562.10 | NP_001346945.1 | |
| G6PD | NM_000402.4 | c.1268G>A | p.Arg423His | missense_variant | Exon 10 of 13 | NP_000393.4 | ||
| G6PD | NM_001042351.3 | c.1178G>A | p.Arg393His | missense_variant | Exon 10 of 13 | NP_001035810.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
25
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
GnomAD4 genome
Cov.:
25
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7Other:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 07, 2021 | This sequence change replaces arginine with histidine at codon 393 of the G6PD protein (p.Arg393His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with glucose-6-phosphate dehydrogenase deficiency (PMID: 1999409, 1536798). ClinVar contains an entry for this variant (Variation ID: 10370). 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. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects G6PD protein function (PMID: 16934959, 19465117, 25407525). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 11, 2023 | - - |
| Pathogenic, criteria provided, single submitter | curation | Dunham Lab, University of Washington | Aug 12, 2022 | Variant found in unrelated hemizygotes with deficiency, acute anemia, and CNSHA (PS4_M, PP4). In one family, heizygous brothers both have deficiency and acute or chronic anemia (PP1). Decreased activity in red blood cells (1-33%) (PS3). Within dimer interface (PM1). Predicted to be deleterious by SIFT, Polyphen, and MutationTaster (PP3). Not found in gnomAD (PM2). Reported as pathogenic by Invitae and ARUP Laboratories (PP5). Post_P 0.9997 (odds of pathogenicity 28416, Prior_P 0.1). - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1992 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion, Medical Genetics | - | The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 1536798, 16934959, 19224086, 25407525). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.84). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000010370 / PMID: 1999409). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 1536798, 1999409). Different missense changes at the same codon (p.Arg393Cys, p.Arg393Gly) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001066811, VCV001722672 / PMID: 7655862). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
not specified Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 20, 2019 | The G6PD c.1178G>A; p.Arg393His variant (rs137852316), also known as G6PD Nashville and G6PD Anaheim, has been reported in the literature in individuals and families with glucose-6-phosphate dehydrogenase (G6PD) deficiency (Beutler 1991, Filosa 1992). This variant is reported as pathogenic in ClinVar (Variation ID: 10370) and is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, another variant at this codon (c.1177C>G; p.Arg393Gly) have been reported in individuals with G6PD deficiency and is considered pathogenic (Beutler 1995). The arginine at codon 393 is highly conserved and computation algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be deleterious. Further, functional analyses demonstrate protein instability and impairment (Gomez-Manzo 2014, Wang 2006, Wang 2009). Based on the above information, this variant is considered pathogenic. References: Beutler E et al. DNA sequence abnormalities of human glucose-6-phosphate dehydrogenase variants. J Biol Chem. 1991 Mar 5;266(7):4145-50. Beutler E et al. Three new exon 10 glucose-6-phosphate dehydrogenase mutations. Blood Cells Mol Dis. 1995;21(1):64-72. Filosa S et al. Molecular basis of chronic non-spherocytic haemolytic anaemia: a new G6PD variant (393 Arg----His) with abnormal KmG6P and marked in vivo instability. Br J Haematol. 1992 Jan;80(1):111-6. Gomez-Manzo S et al. The Stability of G6PD Is Affected by Mutations with Different Clinical Phenotypes. Int J Mol Sci. 2014 Nov; 15(11): 21179-21201. Wang X et al. Functional properties of two mutants of human glucose 6-phosphate dehydrogenase, R393G and R393H, corresponding to the clinical variants G6PD Wisconsin and Nashville. Biochim Biophys Acta. 2006;1762(8):767-774. Wang X et al. Clinical mutants of human glucose 6-phosphate dehydrogenase: Impairment of NADP+ binding affects both folding and stability. Biochim Biophys Acta. 2009;1792(8):804-809. - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 20, 2023 | PP3, PP5, PM2, PS3, PS4_moderate - |
G6PD ANAHEIM Other:1
| other, no assertion criteria provided | literature only | OMIM | Dec 01, 1990 | - - |
G6PD NASHVILLE Other:1
| other, no assertion criteria provided | literature only | OMIM | Dec 01, 1990 | - - |
G6PD PORTICI Other:1
| other, no assertion criteria provided | literature only | OMIM | Jan 01, 1992 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D;D;.
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;M;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
.;.;D;D
REVEL
Pathogenic
Sift
Pathogenic
.;.;D;D
Sift4G
Pathogenic
D;.;D;D
Polyphen
D;D;D;.
Vest4
MutPred
Loss of MoRF binding (P = 0.1207);Loss of MoRF binding (P = 0.1207);Loss of MoRF binding (P = 0.1207);.;
MVP
MPC
2.3
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at