Submissions for variant NM_000374.5(UROD):c.578G>C (p.Arg193Pro)

dbSNP: rs143823335

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001857846	SCV002248800	likely pathogenic	not provided	2021-08-03	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg193 amino acid residue in UROD. Other variant(s) that disrupt this residue have been observed in individuals with UROD-related conditions (PMID: 19233912), which suggests that this may be a clinically significant amino acid residue. Studies have shown that this missense change alters UROD gene expression (PMID: 11719352). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 254172). This missense change has been observed in individual(s) with porphyria cutanea tarda (PMID: 11719352, 19233912). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with proline at codon 193 of the UROD protein (p.Arg193Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509339	SCV002819463	likely pathogenic	UROD-Related Disorders	2022-12-12	criteria provided, single submitter	clinical testing	Variant summary: UROD c.578G>C (p.Arg193Pro) results in a non-conservative amino acid change located in the Uroporphyrinogen decarboxylase (URO-D) domain (IPR000257) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251414 control chromosomes (gnomAD). c.578G>C has been reported in the literature in multiple individuals affected with Porphyria Cutanea Tarda, specifically in individuals of Norwegian ancestry (Phillips_2001, Aarsand_2009). These data indicate that the variant is very likely to be associated with disease. When the variant was expressed in an E. coli expression system, the resulting variant protein was insoluble (Phillips_2001). UROD is typically soluble, strongly suggesting the variant alters the structure of the final protein. One ClinVar submitter has assessed the variant since 2014: the variant was classified as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneReviews	RCV000240668	SCV000299278	not provided	Familial porphyria cutanea tarda		no assertion provided	literature only