ClinVar Miner

Submissions for variant NM_000531.6(OTC):c.540+265G>A (rs1555975756)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626698 SCV000747401 pathogenic Protein avoidance; Abnormality of ornithine metabolism; Hyperammonemia 2017-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000521922 SCV000617478 pathogenic not provided 2016-03-02 criteria provided, single submitter clinical testing The c.540+265 G>A variant in the OTC gene has been reported previously in association with neonatal onset ornithine transcarbamylase (OTC) deficiency in hemizygous males (Ogino et al. 2007; Engel et al. 2008). mRNA analysis of c.540+265 G>A found that this variant results in an insertion of 135 bases in intron 5, creates a new splice acceptor site and leads to the creation of a new in-frame Stop codon, which causes loss of normal protein function through nonsense-mediated mRNA decay (Ogino et al. 2007; Engel et al. 2008). The c.540+265 G>A variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. In summary, we interpret c.540+265 G>A to be a pathogenic variant, and its presence is consistent with the diagnosis of OTC deficiency in this individual. Approximately 20% of females who are heterozygous for variants in the OTC gene are clinically symptomatic with disease severity similar to males with partial deficiency (Yamaguchi et al., 2006; Tuchman et al., 2002).
Invitae RCV000548908 SCV000631860 pathogenic Ornithine carbamoyltransferase deficiency 2018-12-31 criteria provided, single submitter clinical testing This sequence change falls in intron 5 of the OTC gene. It does not directly change the encoded amino acid sequence of the OTC protein. This variant has been reported in individuals affected with OTC deficiency (PMID:  18204299,  18440262, Invitae). Experimental study have shown that this variant interferes with RNA splicing and results in an insertion of 135 nucleotides between exons 5 and 6 of the OTC mRNA. This introduces a premature stop codon which is expected to create truncated protein products with loss of enzymatic activity (PMID: 18204299, 18440262). Loss-of-function variants in OTC are known to be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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