ClinVar Miner

Submissions for variant NM_000531.6(OTC):c.674C>T (p.Pro225Leu) (rs67120076)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000083536 SCV000330994 pathogenic not provided 2015-11-03 criteria provided, single submitter clinical testing
Invitae RCV000011747 SCV000825697 pathogenic Ornithine carbamoyltransferase deficiency 2018-09-05 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 225 of the OTC protein (p.Pro225Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with ornithine transcarbamylase (OTC) deficiency in a family (PMID: 1721894) and has been reported in individuals affected with this condition (PMID: 27070778, 9427144, 9286441). ClinVar contains an entry for this variant (Variation ID: 11000). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Other missense substitutions at this codon (p.PRo225Arg and p.Pro225Thr) have been reported in individuals affected with ornithine transcarbamylase (OTC) deficiency (PMID: 9427144, 19669271, 10946359). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America 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.
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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