ClinVar Genomic variation as it relates to human health

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital erythropoietic porphyria (MIM#263700). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 62 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated HEM4 family domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been well reported as pathogenic, and as homozygous and compound heterozygous in affected individuals (ClinVar, PMIDs: 34828434, 31843562, 15065102, 30685241). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies showed the C73R enzyme had markedly decreased UROS activity (PMID: 21570665). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 73 of the UROS protein (p.Cys73Arg). This variant is present in population databases (rs121908012, gnomAD 0.04%). This missense change has been observed in individual(s) with congenital erythropoietic porphyria (PMID: 1737856, 8821859, 22816431, 23557135, 25092523, 27859603). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3750). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on UROS protein function. Experimental studies have shown that this missense change affects UROS function (PMID: 16532394, 19099412, 21343304). For these reasons, this variant has been classified as Pathogenic.

Across a selection of the available literature, the UROS c.217T>C (p.Cys73Arg) missense variant has been identified in 17 individuals with congenital erythropoietic porphyria, including in six in a homozygous state, in seven in a compound heterozygous state, and in four in a heterozygous state (Deybach et al. 1990; Boulechfar et al. 1992; Warner et al. 1992; Xu et al. 1995; Frank et al. 1998). The p.Cys73Arg variant was also found in a heterozygous state in ten unaffected family members (Deybach et al. 1990; Boulechfar et al. 1992; Warner et al. 1992; Xu et al. 1995; Frank et al. 1998). The variant was absent from the only two controls tested and is reported at a frequency of 0.00069 in the European American population of the Exome Sequencing Project. Expression of the p.Cys73Arg variant in E. coli showed less than 2% residual protein activity (Boulechfar et al. 1992; Warner et al. 1992). Fortian et al. (2011) demonstrated that the p.Cys73Arg variant leads to irreversible enzyme unfolding and aggregation while Bishop et al. (2011) showed that knock-in mice homozygous for the p.Cys73Arg variant had a severe phenotype. Based on the collective evidence, the p.Cys73Arg variant is classified as pathogenic for congenital erythropoietic porphyria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting

The UROS c.217T>C variant is predicted to result in the amino acid substitution p.Cys73Arg. This variant has been reported to be causative for congenital erythropoietic porphyria (Xu et al. 1995. PubMed ID: 7860775; Deybach et al. 1990. PubMed ID: 2331520; Glomglao et al. 2015. PubMed ID: 25092523). Homozygous mouse models of the p.Cys73Arg variant resulted in severe microcytic hypochromic anemia and congenital erythropoietic porphyria (Bishop et al. 2011. PubMed ID: 21365124). This variant is reported in 0.041% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.

Most common UROS pathogenic variant observed in approximately one-third of affected persons.