ClinVar Genomic variation as it relates to human health

Variant summary: UROS c.10C>T (p.Leu4Phe) results in a non-conservative amino acid change located in the Tetrapyrrole biosynthesis, uroporphyrinogen III synthase domain (IPR003754) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251476 control chromosomes (gnomAD). c.10C>T has been reported in the literature in multiple bi-allelic individuals affected with Cutaneous Porphyria (examples: Boulechfar_1992, Xu_1995, Katugampola_2012, and Ciftci_2018). These data indicate that the variant is very likely to be associated with disease. Multiple publications have reported experimental evidence that this variant reduces normal activity of the protein (examples: Fortian_2009, and Boulechfar_1992). The following publications have been ascertained in the context of this evaluation (PMID: 1733834, 7860775 , 30706587, 22816431, 19099412). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change replaces leucine with phenylalanine at codon 4 of the UROS protein (p.Leu4Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects UROS protein function (PMID: 1733834, 19099412). This variant has been observed in individual(s) with congenital erythropoietic porphyria (PMID: 1733834, 30706587, 7860775). ClinVar contains an entry for this variant (Variation ID: 3755). This variant is present in population databases (rs121908015, ExAC 0.004%).

The UROS c.10C>T variant is predicted to result in the amino acid substitution p.Leu4Phe. This variant has been reported in the homozygous or compound heterozygous states in multiple individuals with congenital erythropoietic porphyria (Boulechfar et al 1992. PubMed ID: 1733834; Ciftci et al 2019. PubMed ID: 30706587; Xu et al 1995. PubMed ID: 7860775). In vitro experimental studies suggest this variant impacts protein function (Fortian et al 2009. PubMed ID: 19099412; Blouin et al 2017. PubMed ID: 28334762). This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-127505059-G-A). This variant is interpreted as pathogenic.