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

dbSNP: rs72554665

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000354491	SCV000330997	pathogenic	not provided	2015-08-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778152	SCV000914284	pathogenic	G6PD 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	RCV001212765	SCV001367223	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2019-08-20	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001212765	SCV001384362	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-12-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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, 2263506, 6714986, 8537082, 10643148, 11499668, 17726510, 20203002, 21446359, 25541721, 25775246, 26823837). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 10422). This variant is also known as Cosenza variant. This missense change has been observed in individual(s) with G6PD deficiency (PMID: 8447319, 9299858, 23365477). This variant is present in population databases (rs72554665, gnomAD 0.001%). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 459 of the G6PD protein (p.Arg459Pro).
Dunham Lab, University of Washington	RCV001212765	SCV002599394	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-08-12	criteria provided, single submitter	curation	Variant found in unrelated hemizygotes with deficiency, some with favism and anemia (PS4_M, PP4). Decreased activity in red blood cells (1-14%) (PS3). Affects same amino acid as pathogenic 459R>L (ClinVar ID 100058) (PM5). Below expected carrier frequency in gnomAD (PM2). Reported as pathogenic by Eurofins (PP5). Post_P 0.999 (odds of pathogenicity 6568, Prior_P 0.1).
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	RCV001212765	SCV003930291	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-06-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460459	SCV004195409	pathogenic	Malaria, susceptibility to	2024-02-05	criteria provided, single submitter	clinical testing
OMIM	RCV000011167	SCV000031394	other	G6PD COSENZA	2017-05-24	no assertion criteria provided	literature only