ClinVar Miner

Submissions for variant NM_000375.3(UROS):c.673G>A (p.Gly225Ser)

gnomAD frequency: 0.00006  dbSNP: rs121908020
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001851635 SCV002210642 pathogenic not provided 2023-12-02 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 225 of the UROS protein (p.Gly225Ser). This variant is present in population databases (rs121908020, gnomAD 0.006%). This missense change has been observed in individuals with congenital erythropoietic porphyria (PMID: 7860775, 16365260). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3766). 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) performed at Invitae indicates that this missense variant is not expected to disrupt UROS protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects UROS function (PMID: 7860775, 19099412). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000003964 SCV005400407 pathogenic Cutaneous porphyria 2024-10-09 criteria provided, single submitter clinical testing 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 glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes). (SP) 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 domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed as compound heterozygous in at least eight individuals with congenital erythropoietic porphyria (PMIDs: 38255745, 28334762, 16365260, 22816431, 30685241, 12060112). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM RCV000003964 SCV000024129 pathogenic Cutaneous porphyria 2001-03-01 no assertion criteria provided literature only
GeneReviews RCV000003964 SCV000086783 not provided Cutaneous porphyria no assertion provided literature only

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