ClinVar Miner

Submissions for variant NM_000402.4(G6PD):c.1466G>C (p.Arg489Pro) (rs72554665)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000354491 SCV000330997 pathogenic not provided 2015-08-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778152 SCV000914284 pathogenic Glucose 6 phosphate dehydrogenase deficiency 2019-04-05 criteria provided, single submitter clinical testing Across a selection of available literature, the G6PD c.1376G>C (p.Arg459Pro) missense variant, also referred to as c.1466G>C (p.Arg489Pro) or the "Cosenza" variant, has been reported in at least 24 individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency (Calabro et al. 1993; Barisic et al. 2005; Moosazadeh et al. 2013; Javadi et al. 2015). The p.Arg459Pro variant has been identified in multiple ethnic populations from countries around the Mediterranean (including Italy and Iran) and is most prevalent in Croatia. This variant is associated with a severe form of G6PD enzyme deficiency (Calabro et al. 1993; Moosazadeh et al. 2013). Control data are not available for this variant, which is reported at a frequency of 0.000248 in the Other population of the Genome Aggregation Database but this is based on one allele in a region of good sequencing coverage so the variant is presumed to be rare in the general population. Functional assays demonstrate that the p.Arg459Pro variant results in reduced enzyme activity, between 2% and 9.5% of normal (Calabro et al. 1993; Barisic et al. 2005). Based on the collective evidence, the p.Arg489Pro 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.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196615 SCV001367223 pathogenic Myopathy; Meningioma; Cataract (disease); Osteoporosis; Hypertensive disorder 2019-08-20 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3. This variant was detected in heterozygous state.
Invitae RCV001212765 SCV001384362 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2019-08-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 459 of the G6PD protein (p.Arg459Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. This variant is present in population databases (rs72554665, ExAC 0.002%). This variant has been observed in several individuals affected with G6PD deficiency (PMID: 8447319, 9299858, 23365477). This variant is also known in the literature as Cosenza variant. ClinVar contains an entry for this variant (Variation ID: 10422). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg459 amino acid residue in G6PD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1562739, 10643148, 2263506, 6714986, 26823837, 25775246, 25541721, 17726510, 20203002, 11499668, 8537082, 21446359). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000011167 SCV000031394 other G6PD COSENZA 2017-05-24 no assertion criteria provided literature only

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