chrX-154536168-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong
The NM_001360016.2(G6PD):āc.131C>Gā(p.Ala44Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000111 in 1,209,580 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 73 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Consequence
NM_001360016.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
G6PD | NM_001360016.2 | c.131C>G | p.Ala44Gly | missense_variant | Exon 3 of 13 | ENST00000393562.10 | NP_001346945.1 | |
G6PD | NM_000402.4 | c.221C>G | p.Ala74Gly | missense_variant | Exon 3 of 13 | NP_000393.4 | ||
G6PD | NM_001042351.3 | c.131C>G | p.Ala44Gly | missense_variant | Exon 3 of 13 | NP_001035810.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000116 AC: 13AN: 111652Hom.: 0 Cov.: 23 AF XY: 0.000237 AC XY: 8AN XY: 33820
GnomAD3 exomes AF: 0.000169 AC: 31AN: 183304Hom.: 0 AF XY: 0.000295 AC XY: 20AN XY: 67784
GnomAD4 exome AF: 0.000110 AC: 121AN: 1097872Hom.: 0 Cov.: 31 AF XY: 0.000179 AC XY: 65AN XY: 363234
GnomAD4 genome AF: 0.000116 AC: 13AN: 111708Hom.: 0 Cov.: 23 AF XY: 0.000236 AC XY: 8AN XY: 33886
ClinVar
Submissions by phenotype
Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:7
Variant found in unrelated hemizygotes with deficiency, some with anemia and jaundice (PP4, PS4_M). In one family, hemiygote and heterozygous mother both have decreased G6PD activity (PP1). Decreased activity in red blood cells (5-33%) (PS3). In GxxGDLA NADP binding site (PM1). Predicted to be damaging by SIFT and MutationTaster, and probably damaging by PolyPhen (PP3). Below expected carrier frequency in gnomAD (PM2). Post_P 0.999 (odds of pathogenicity 13661, Prior_P 0.1). -
- -
This variant in exon 3 of the G6PD gene results in the amino acid substitution from Alanine to Glycine at codon 74 (p.Ala74Gly) with the sequence change of c.221C>G (NM_000402.4). This variant was observed in a proband with decreased level of G6PD enzyme (<2.4 U/dL) which was screened for advanced newborn screening with confirmatory genetic reflex testing at lifecell diagnostics. The reference base is conserved across the species and in-silico predictions by SIFT and MutationTaster are damaging. The Missense Variants Z-Score for this variant is 2.60. Missense Variants Z-Score is produced by the Exome Aggregation Consortium (60,706 adult humans) by computing a signed Z score for the deviation of observed counts from the expected number. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer missense variants than expected. The G6PD c.221C>G; p.Ala74Gly variant, also referred to as c.131C>G; p.Ala44Gly, commonly known as G6PD Orissa, has been described in literatures as a Class III variant, associated with moderate enzyme deficiency (Arunachalam et al., 2020; PMID: 32425388, Minucci et al., 2010; PMID: 20621077). This variant has previously been reported for glucose-6-phosphate dehydrogenase deficiency and is most frequent in Indian tribal population (Kaeda et al., 1995; PMID:8533762, Sukumar et al., 2004; PMID:15315792, Lin et al., 2016; PMID:26829728, Sarker et al., 2016; PMID:27880809). Experimental studies have shown that this missense change reduces G6PD enzymatic activity in vitro (Kaeda et al., 1995; PMID:8533762). -
This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 44 of the G6PD protein (p.Ala44Gly). This variant is present in population databases (rs78478128, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with glucose-6-phosphate dehydrogenase deficiency (PMID: 10192449, 17524386). It is commonly reported in individuals of South Asian ancestry (PMID: 8533762, 15315792, 20621077, 22906047, 26829728, 27880809). ClinVar contains an entry for this variant (Variation ID: 10406). 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) 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: 8533762). For these reasons, this variant has been classified as Pathogenic. -
The missense c.221C>G (p.Ala74Gly) variant in G6PD gene has been reported in heterozygous state in individuals affected with hemolytic anemia. This variant has been reported to be a common cause of the glucose-6-phosphate dehydrogenase in South Asia, although it has also been reported in other populations (Sukumar et al., 2004). Experimental studies have shown that this missense change reduces G6PD enzymatic activity in vitro (Kaeda et al., 1995). This variant is reported with the allele frequency 0.01% in the gnomAD and 0.02% in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Pathogenic / Uncertain Significance. The amino acid Ala at position 74 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Ala74Gly in G6PD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
- -
A heterozygous missense variation in exon 3 of the G6PD gene that results in the amino acid substitution of Glycine for Alanine at codon 44 was detected. The observed variant c.131C>G (p.Ala44Gly) has a minor allele frequency of 0.03%, 0.01%, 0.02% and 0.003% in the 1000 genomes, gnomAD (v3.1), gnomAD (v2.1) and topmed databases, respectively. The insilico predictions of the variant are probably damaging by PolyPhen-2 and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of pathogenic. -
not provided Pathogenic:4
- -
G6PD: PM1:Strong, PM5, PS3:Moderate, PS4:Moderate -
Functional analysis of recombinant enzyme showed significantly increased Km-NADP and increased thermostability (Kaeda et al., 1995); Also known as G6PD Orissa (Kaeda et al., 1995; Sarker et al., 2016); This variant is associated with the following publications: (PMID: 21507207, 27880809, 21931771, 8533762, 30097005, 20621077, 15315792, 2255919, 26829728, 26139767, 26021654, 12497642, 21446359, 33069889, 12215013) -
The G6PD c.131C>G; p.Ala44Gly variant (rs78478128, ClinVar Variation ID: 10406), also known as G6PD Orissa, is reported in the literature in individuals affected with G6PD deficiency (Devendra 2020, Islam 2018, Kaeda 1995, Sarker 2016) and is classified as a class III variant associated with mild to moderate G6PD enzyme deficiency (Arunachalam 2020). This variant is found in the South Asian population with an allele frequency of 0.16% (31/19076 alleles, including 20 hemizygotes) in the Genome Aggregation Database (v2.1.1). Functional analyses of the variant protein show reduced G6PD enzymatic activity (Kaeda 1995). Additionally computational analyses predict that this variant is deleterious (REVEL: 0.967). Based on available information, this variant is considered to be pathogenic. References: Arunachalam AK et al. Molecular Characterization of G6PD Deficiency: Report of Three Novel G6PD Variants. Indian J Hematol Blood Transfus. 2020 Apr;36(2):349-355. PMID: 32425388. Kaeda JS et al. A new glucose-6-phosphate dehydrogenase variant, G6PD Orissa (44 Ala-->Gly), is the major polymorphic variant in tribal populations in India. Am J Hum Genet. 1995 Dec;57(6):1335-41. PMID: 8533762. Sarker SK et al. Molecular Analysis of Glucose-6-Phosphate Dehydrogenase Gene Mutations in Bangladeshi Individuals. PLoS One. 2016 Nov 23;11(11):e0166977. PMID: 27880809. Islam MT et al. High resolution melting curve analysis enables rapid and reliable detection of G6PD variants in heterozygous females. BMC Genet. 2018 Aug 10;19(1):58. PMID: 30097005. Devendra R et al. Prevalence and spectrum of mutations causing G6PD deficiency in Indian populations. Infect Genet Evol. 2020 Dec;86:104597. PMID: 33069889. -
Malaria, susceptibility to;C2720289:Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:1
- -
Malaria, susceptibility to Pathogenic:1
- -
G6PD deficiency Pathogenic:1
The G6PD c.221C>G (p.Ala74Gly) missense variant, also known as c.131C>G (p.Ala44Gly) or the G6PD Orissa allele, has been commonly reported in individuals with glucose-6-phosphate dehydrogenase deficiency with South Asian ancestry, including in a hemizygous and homozygous state (PMID: 27880809; 8533762; 32425388). Enzyme activity in individuals with this variant is typically 5%-20% of normal. The highest frequency of this allele in the Genome Aggregation Database is 0.004917 in the South Asian population, which includes eight hemizygotes (version 3.1.2). This frequency is consistent with disease prevalence estimates. Functional studies of purified enzyme have demonstrated that this variant causes an increase in Km for NADP+, which results in a reduced G6PD enzyme activity level (PMID: 8533762). This variant has been classified as pathogenic by at least three submitters in ClinVar. Based on the available evidence, the c.221C>G (p.Ala74Gly) variant is classified as pathogenic for glucose-6-phosphate dehydrogenase deficiency. -
G6PD ORISSA Other:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at