ClinVar Miner

Submissions for variant NM_000531.6(OTC):c.674C>T (p.Pro225Leu)

dbSNP: rs67120076
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000083536 SCV000330994 pathogenic not provided 2015-11-03 criteria provided, single submitter clinical testing
Invitae RCV000011747 SCV000825697 pathogenic Ornithine carbamoyltransferase deficiency 2022-11-01 criteria provided, single submitter clinical testing This missense change has been observed in individuals with ornithine transcarbamylase (OTC) deficiency (PMID: 1721894, 9286441, 9427144, 27070778). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 225 of the OTC protein (p.Pro225Leu). ClinVar contains an entry for this variant (Variation ID: 11000). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro225 amino acid residue in OTC. Other variant(s) that disrupt this residue have been observed in individuals with OTC-related conditions (PMID: 9427144, 10946359, 19669271), which suggests that this may be a clinically significant amino acid residue. 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 expected to disrupt OTC protein function.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000011747 SCV001364018 pathogenic Ornithine carbamoyltransferase deficiency 2019-08-29 criteria provided, single submitter clinical testing Variant summary: OTC c.674C>T (p.Pro225Leu) results in a non-conservative amino acid change located in the Aspartate/ornithine carbamoyltransferase, Asp/Orn-binding domain (IPR006131) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182904 control chromosomes (gnomAD). The variant, c.674C>T, has been reported in the literature in multiple individuals affected with Ornithine Transcarbamylase Deficiency (OTCD) (Hentzen_1991, Garcia-Perez_1997, Matsuda_1997, McCullough_2000, Bijarnia-Mahay_2018). Hentzen_1991 reported this variant to segregate with OTCD in one family. These data indicate that the variant is very likely to be associated with disease. Several publications also reported (near) undetectable residual enzyme activities from patient samples (Hentzen_1991, Garcia-Perez_1997, Matsuda_1997, McCullough_2000). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic (1x) or pathogenic (2x). Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab RCV000011747 SCV002033227 pathogenic Ornithine carbamoyltransferase deficiency 2021-11-07 criteria provided, single submitter clinical testing
OMIM RCV000011747 SCV000031979 pathogenic Ornithine carbamoyltransferase deficiency 1991-12-01 no assertion criteria provided literature only
GenMed Metabolism Lab RCV000083536 SCV000115622 pathogenic not provided no assertion criteria provided not provided Converted during submission to Pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000011747 SCV000268692 likely pathogenic Ornithine carbamoyltransferase deficiency 2016-05-09 no assertion criteria provided clinical testing

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