ClinVar Miner

Submissions for variant NM_000402.4(G6PD):c.1039G>A (p.Glu347Lys) (rs137852339)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000800624 SCV000940353 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 317 of the G6PD protein (p.Glu317Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs137852339, ExAC 1.2%). This variant is a prevalent G6PD variant in the South Asian population, typically associated with partial reduction of enzyme activity (PMID: 1303182, 30097005, 16528451, 15315792, 30097005, 27880809, 27535533). By WHO classification, this is a Class III variant associated with moderate G6PD deficiency (10-60% enzyme activity) and hemolysis with stressors only (PMID: 22293322). This variant is also known as G6PD Kerala, G6PD Kalyan, G6PD Kerala–Kalyan, G6PD Jamnaga, and G6PD Rohini in the literature. ClinVar contains an entry for this variant (Variation ID: 10401). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000800624 SCV001142106 uncertain significance Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2019-05-28 criteria provided, single submitter clinical testing
LifeCell International Pvt. Ltd RCV000800624 SCV001443093 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 glutamic acid to lysine at codon 347 (p.Glu347Lys) with the sequence change of c.1039G>A (NM_000402.4). This variant was observed in a proband with a decreased level of G6PD enzyme (3.1 U/dl) which was screened for advanced newborn screening with confirmatory genetic reflex testing at Lifecell diagnostics. There is a small physicochemical difference between glutamic acid and lysine. The observed variant is not present in both the 1000 Genomes and gnomAD databases. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT are damaging. This is a Class III variant associated with moderate G6PD deficiency (10-60% enzyme activity) and hemolysis with stressors only. According to the previous studies this variant is also known as G6PD Kerala, G6PD Kalyan, G6PD Kerala Kalyan, G6PD Jamnaga, and G6PD Rohini. This variant has previously been reported for Glucose-6- phosphate dehydrogenase (G6PD) deficiency by Islam MT et al., 2018. 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. This variant is a prevalent G6PD variant in the South Asian population, typically associated with partial reduction of enzyme activity (Ahluwalia A et al. 1992; PMID: 1303182), (Islam MT et al. 2018; PMID: 30097005), ( Ninokata A et al, 2006; PMID: 16528451), ( Sukumar S et al. 2004; PMID: 15315792), ( Sarker SK et al. 2016; PMID: 27880809), (Minucci A et al, 2012; PMID: 22293322).
Illumina Clinical Services Laboratory,Illumina RCV001563664 SCV001786652 pathogenic Glucose 6 phosphate dehydrogenase deficiency 2021-03-05 criteria provided, single submitter clinical testing The G6PD c.1039G>A (p. Glu347Lys) missense variant, which is also commonly reported as c.949G>A (p.Glu317Lys) and G6PD Kerala-Kalyan, and less commonly reported as G6PD Jamnagar or Rohini, is one of the most common disease-causing variants in South Asian populations. The p.Glu347Lys variant has been estimated to account for between 1.1% and 24.5% of disease-causing alleles in the Indian population (Sukumar et al. 2004; Devendra et al. 2020). This variant has also been reported in affected individuals of Bangladeshi, Burmese, and Thai descent (Nuchprayoon et al. 2008; Sarker et al. 2016). The p.Glu347Lys variant is typically associated with glucose-6-phosphate dehydrogenase enzyme activity levels between 10% - 60% of wild type and is considered a class III variant according the WHO classification system for G6PD variants (Minucci et al. 2012; Harcke et al. 2019). The p.Glu347Lys variant is reported at a frequency of 0.01138 in the South Asian population of the Genome Aggregation Database. This allele frequency is high but is consistent with the disease prevalence estimates. Although the consequences of p.Glu347Lys have not been characterized experimentally, the Glu347 residue is known to interact with Lys275, which is the site of the another disease-causing variant, p.Lys275Asn or G6PD Bangkok. This interaction forms a salt bridge between subunits B and C of the tetrameric structure in wild-type G6PD (Boonyuen et al. 2017). Based on the collective evidence and application of the ACMG criteria, the p. Glu347Lys variant is classified as pathogenic for glucose-6-phosphate dehydrogenase deficiency.
OMIM RCV000011142 SCV000031369 other G6PD KERALA-KALYAN 2013-04-18 no assertion criteria provided literature only
OMIM RCV000011143 SCV000031370 other G6PD KERALA 2013-04-18 no assertion criteria provided literature only
OMIM RCV000011144 SCV000031371 other G6PD KALYAN 2013-04-18 no assertion criteria provided literature only

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