ClinVar Miner

Submissions for variant NM_000402.4(G6PD):c.961G>A (p.Val321Met) (rs137852327)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000757320 SCV000233009 pathogenic not provided 2015-08-05 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000405688 SCV000482072 pathogenic Glucose 6 phosphate dehydrogenase deficiency 2017-04-28 criteria provided, single submitter clinical testing The G6PD c.871G>A (p.Val291Met) variant, also referred to as c.961G>A (p.Val321Met), is well described in the literature as a common variant across several Asian populations and is often referred to as G6PD Viangchan or G6PD Jammu. The variant was first identified in an individual of Laotian ancestry with glucose-6-phosphate dehydrogenase (G6PD) deficiency (Beutler et al. 1991) and has since been reported as the most common G6PD variant in the Thai and Cambodian populations: Nuchprayoon et al. (2002) identified the p.Val291Met variant in 43 of 76 Thai G6PD deficiency patients, while the variant was reported in a total of 74 of 81 Cambodian G6PD deficiency patients (Matsuoka et al. 2005; Louicharoen et al. 2005). Control data are not reported in these studies for the p.Val291Met variant, which is reported at a frequency of 0.00785 in the East Asian population of the 1000 Genomes Project. Boonyuen et al. (2016) expressed the p.Val291Met variant in E. coli and reported that the KM for glucose-6-phosphate was similar to that of the wild type protein, though the KM for NADP+ was 5-fold higher than wild type and the kcat showed a 10-fold reduction in catalytic efficiency for NADP+ catalysis. Additionally, the variant showed significantly reduced thermostability as compared to wild type. Based on the collective evidence, the p.Val291Met variant is classified as pathogenic for glucose-6-phosphate dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Counsyl RCV000180545 SCV000677920 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2017-06-15 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757320 SCV000885495 pathogenic not provided 2017-08-17 criteria provided, single submitter clinical testing The G6PD c.871G>A; p.Val291Met variant (rs137852327), commonly known as G6PD Viangchan, has been described in the literature as a Class II to Class III pathogenic variant and is associated with a moderate to severe decrease in enzyme activity (Beutler 1994, Hue 2009, Nuchprayoon 2002). It is listed in ClinVar (Variation ID: 10386) and observed in the general population databases at a frequency of 0.16 percent in the 1000 Genomes Project (6/3775 alleles) and 0.02 percent in the Genome Aggregation Database (40/199860 alleles). The valine residue is highly conserved and computational programs (SIFT, PolyPhen2, MutationTaster) predict this variant to be deleterious to protein function. Taken together we consider this variant to be pathogenic. REFERENCES Beutler E. G6PD deficiency. Blood. 1994 Dec 1;84(11):3613-36. Hue NT et al. Glucose-6-phosphate dehydrogenase (G6PD) mutations and haemoglobinuria syndrome in the Vietnamese population. Malar J. 2009 Jul 10;8:152. Nuchprayoon I et al. Glucose-6-phosphate dehydrogenase (G6PD) mutations in Thailand: G6PD Viangchan (871G>A) is the most common deficiency variant in the Thai population. Hum Mutat. 2002 Feb;19(2):185.
Fulgent Genetics,Fulgent Genetics RCV000763203 SCV000893822 pathogenic Susceptibility to malaria; Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000180545 SCV000951744 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 291 of the G6PD protein (p.Val291Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant has been observed as the most common G6PD deficiency mutation in certain Cambodian, Chinese, and Malay populations (PMID: 16155737, 15906717, 18329300). ClinVar contains an entry for this variant (Variation ID: 10386). Experimental studies have shown that this missense change impairs G6PD enzyme activity in vitro (PMID: 27213370, 3338798). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000180545 SCV000966815 likely pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2017-06-19 criteria provided, single submitter clinical testing The p.Val321Met (NM_000402.3 c.961G>A) (also referred to as c.871G>A, p.Val291Me t on NM_001042351, G6PD Viangchan and G6PD Jammu) variant in G6PD is one of the most common variants associated with Glucose-6-phosphate dehydrogenase (G6PD) de ficiency in the Asian population and has been reported in several males (hemizyg ous) and females (heterozygous, compound heterozygous, and homozygous) with G6PD deficiency (Beutler 1991, Peng 2005, Ko 2006, Ninokata 2006, Li 2008, Nuchpray oon 2008, Natakomol 2013, Li 2015). It should be noted that most individuals rep orted with this variant were identified through screening by enzyme testing of a pparently healthy individuals at the time of the study. This variant has been re ported in ClinVar (Variation ID#10386) as a pathogenic variant. It has been ide ntified in 0.24% (33/13881) of East Asian chromosomes including 14 hemizygotes b y the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; db SNP rs137852327). In vitro functional studies provide evidence that the p.Val321 Met variant may impact protein function (Boonyuen 2016 and Gomez-Manzo 2016). In summary, although additional studies are required to fully establish its clinic al significance, this variant is likely pathogenic for G6PD deficiency in an X-l inked manner based upon its occurrence in individuals with this disorder and da ta from functional studies.
Centogene AG - the Rare Disease Company RCV001250220 SCV001424422 pathogenic G6PD deficient hemolytic anemia criteria provided, single submitter clinical testing
LifeCell International Pvt. Ltd RCV000180545 SCV001443091 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency criteria provided, single submitter clinical testing This variant in exon 9 of the G6PD gene results in the amino acid substitution from Valine to Methionine at codon 321 (p.Val321Met) with the sequence change of c.961G>A (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 variant was first identified with glucose-6-phosphate dehydrogenase ( G6PD) deficiency in a person of Laotian ancestry (Beutler et al . 1991) and has since been recorded as the most common variant of G6PD in the Thai and Cambodian populations. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT 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.961G>A; p.Val321Met variant, also referred to as c.871G>A; p.Val291Met, commonly known as G6PD Viangchan, has been described in the literature as a Class II to Class III pathogenic variant and is associated with a moderate to severe decrease in enzyme activity (Hue et al., 2009; PMID: 19589177, Nuchprayoon et al., 2002; PMID: 11793482). This variant is one of the most common variants associated with Glucose-6-phosphate dehydrogenase (G6PD) deficiency in the Asian population (Beutler et al.,1991; PMID: 1805484, Peng et al., 2005; PMID: 25775246, Ko et al., 2006; PMID: 16777444, Ninokata et al., 2006; PMID: 16528451, Li et al., 2008; PMID: 18329300, Nuchprayoon et al., 2008; PMID: 18046504, Nantakomol et al., 2013; PMID: 23965028, Li et al., 2015; PMID: 26226515). Experimental studies have shown that this missense change impairs G6PD enzyme activity in vitro (Gomez-Manzo et al., 2016; PMID: 27213370 and Boonyuen 2016 et al., PMID: 27053284).
Ambry Genetics RCV001266092 SCV001444264 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing
GeneDx RCV000757320 SCV001874266 pathogenic not provided 2021-07-14 criteria provided, single submitter clinical testing Reported to be a common pathogenic variant in Southeast Asian populations (Nuchprayoon et al., 2002); Published functional studies demonstrate that this variant is associated with lower catalytic constant and catalytic efficiency (Gomez-Manzo et al., 2016); This variant is associated with the following publications: (PMID: 11793482, 16155737, 29339739, 27213370, 27535533, 31180159, 30609409, 1805484, 16777444, 18329300, 23313052, 25440321, 25536053, 12850494, 11499668, 16136268, 3338798, 30161219, 29783823, 30315739, 26226515, 25775246, 29702993, 27053284)
OMIM RCV000011116 SCV000031343 other G6PD VIANGCHAN 2017-05-24 no assertion criteria provided literature only
OMIM RCV000011117 SCV000031344 other G6PD JAMMU 2017-05-24 no assertion criteria provided literature only

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