ClinVar Miner

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

dbSNP: rs1555975756
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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 2022-09-21 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 449382). This variant has been observed in individual(s) with ornithine transcarbamylase (OTC) deficiency (PMID: 18204299, 18440262, 33489762). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000626698 SCV000747401 pathogenic Protein avoidance; Abnormal circulating ornithine concentration; Hyperammonemia 2017-01-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000548908 SCV001368080 pathogenic Ornithine carbamoyltransferase deficiency 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic.
Mendelics RCV000548908 SCV002517834 pathogenic Ornithine carbamoyltransferase deficiency 2022-05-04 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV000548908 SCV002581227 pathogenic Ornithine carbamoyltransferase deficiency 2021-11-09 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000548908 SCV004357050 pathogenic Ornithine carbamoyltransferase deficiency 2023-03-08 criteria provided, single submitter clinical testing This variant causes a G to A nucleotide substitution at the +265 position of intron 5 of the OTC gene. This variant has been reported in three male neonates clinically diagnosed with OTC deficiency (PMID: 18204299, 18440262, 34014569), as well as in seven females affected with late-onset OTC deficiency (PMID: 33489762) and episodic OTC deficiency (PMID: 34014569). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). RT-PCR analyses of patient-derived RNA have shown that a new splice acceptor site created by this variant is paired with a cryptic splice donor site located 135 nucleotides downstream, resulting in the inclusion of the 135-nucleotide intronic sequence between exons 5 and 6 of the OTC transcript with a premature stop of translation at codon 184 (PMID: 18204299, 18440262). This variant is expected to result in an absent or nonfunctional protein product. Loss of OTC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000548908 SCV004806270 uncertain significance Ornithine carbamoyltransferase deficiency 2024-03-25 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000548908 SCV004834032 pathogenic Ornithine carbamoyltransferase deficiency 2023-07-19 criteria provided, single submitter clinical testing This variant causes a G to A nucleotide substitution at the +265 position of intron 5 of the OTC gene. This variant has been reported in three male neonates clinically diagnosed with OTC deficiency (PMID: 18204299, 18440262, 34014569), as well as in seven females affected with late-onset OTC deficiency (PMID: 33489762) and episodic OTC deficiency (PMID: 34014569). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). RT-PCR analyses of patient-derived RNA have shown that a new splice acceptor site created by this variant is paired with a cryptic splice donor site located 135 nucleotides downstream, resulting in the inclusion of the 135-nucleotide intronic sequence between exons 5 and 6 of the OTC transcript with a premature stop of translation at codon 184 (PMID: 18204299, 18440262). This variant is expected to result in an absent or nonfunctional protein product. Loss of OTC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Natera, Inc. RCV000548908 SCV001458517 pathogenic Ornithine carbamoyltransferase deficiency 2020-09-16 no assertion criteria provided clinical testing

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