ClinVar Miner

Submissions for variant NM_000375.3(UROS):c.683C>T (p.Thr228Met)

gnomAD frequency: 0.00004  dbSNP: rs121908014
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001851631 SCV002232603 pathogenic not provided 2021-08-27 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 228 of the UROS protein (p.Thr228Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs121908014, ExAC 0.02%). This missense change has been observed in individual(s) with congenital erythropoietic porphyria (PMID: 1737856, 7860775, 8946173, 12060141, 22816431). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3754). 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 disruptive. Experimental studies have shown that this missense change affects UROS function (PMID: 1737856, 30685241). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000003952 SCV003828070 uncertain significance Cutaneous porphyria 2022-09-07 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003407267 SCV004106836 likely pathogenic UROS-related condition 2022-08-25 criteria provided, single submitter clinical testing The UROS c.683C>T variant is predicted to result in the amino acid substitution p.Thr228Met. This variant has been reported in the compound heterozygous state in multiple individuals with autosomal recessive erythropoietic porphyria, and functional studies support its pathogenicity (Warner et al 1992. PubMed ID: 1737856; Fortian A et al 2009. PubMed ID: 19099412; Boulechfar S et al 1992. PubMed ID: 1733834; Fontanellas A et al. 1996. PubMed ID: 8946173). This variant is reported in 0.0057% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-127477552-G-A). This variant is interpreted as likely pathogenic.
OMIM RCV000003952 SCV000024117 pathogenic Cutaneous porphyria 1992-01-01 no assertion criteria provided literature only

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