Submissions for variant NM_000375.3(UROS):c.10C>T (p.Leu4Phe)

gnomAD frequency: 0.00003  dbSNP: rs121908015

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851632	SCV002209285	pathogenic	not provided	2024-11-18	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 4 of the UROS protein (p.Leu4Phe). This variant is present in population databases (rs121908015, gnomAD 0.006%). This missense change has been observed in individuals with congenital erythropoietic porphyria (PMID: 1733834, 7860775, 30706587). ClinVar contains an entry for this variant (Variation ID: 3755). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt UROS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects UROS function (PMID: 1733834, 19099412). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000003953	SCV004020593	pathogenic	Cutaneous porphyria	2023-06-26	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000003953	SCV000024118	pathogenic	Cutaneous porphyria	1992-01-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004754241	SCV005348724	pathogenic	UROS-related disorder	2024-05-10	no assertion criteria provided	clinical testing	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.