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

dbSNP: rs1555975756

Total submissions: 8

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.
Natera, Inc.	RCV000548908	SCV001458517	pathogenic	Ornithine carbamoyltransferase deficiency	2020-09-16	no assertion criteria provided	clinical testing