ClinVar Miner

Submissions for variant NM_000531.6(OTC):c.903A>T (p.Leu301Phe)

dbSNP: rs72558462
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001228473 SCV001400873 pathogenic Ornithine carbamoyltransferase deficiency 2022-12-18 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 301 of the OTC protein (p.Leu301Phe). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu301 amino acid residue in OTC. Other variant(s) that disrupt this residue have been observed in individuals with OTC-related conditions (PMID: 26059767), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. ClinVar contains an entry for this variant (Variation ID: 97350). This missense change has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 11793483, 22340867; Invitae).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001228473 SCV001442697 pathogenic Ornithine carbamoyltransferase deficiency 2023-09-20 criteria provided, single submitter clinical testing Variant summary: OTC c.903A>T (p.Leu301Phe) results in a non-conservative amino acid change located in the aspartate/ornithine carbamoyltransferase, Asp/Orn-binding domain (IPR006131) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183317 control chromosomes (gnomAD and publication data). c.903A>T has been reported in the literature in hemizygous individuals affected with Ornithine Transcarbamylase Deficiency (e.g. Climent_2002, Morel_2012, Lung_2022). In addition, at least one publication reports the residual OTC activity in the liver of a hemizygous patient as 3% of normal activity (e.g. Climent_2002). These data indicate that the variant is likely associated with disease. Furthermore, a different variant resulting in the same amino acid change (c.903A>C, p.Leu301Phe) has been reported in a male proband with OTD deficiency whose mother was a carrier and his maternal uncle and brother were both affected (Barbosa-Gouveia_2021), providing supporting evidence for a pathogenic role. The following publications have been ascertained in the context of this evaluation (PMID: 11793483, 35949797, 28324312, 22340867, 34440436). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001228473 SCV002049318 likely pathogenic Ornithine carbamoyltransferase deficiency 2021-06-15 criteria provided, single submitter clinical testing The OTC c.903A>T; p.Leu301Phe variant (rs72558462) is reported in the literature in multiple individuals affected with ornithine transcarbamylase deficiency (Climent 2002, Morel 2012). Functional analyses of the variant protein show residual liver OTC activity of 3% (Capistrano-Estrada 1994, Climent 2002). This variant is also reported in ClinVar (Variation ID: 97350). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, another variant at this codon (c.902T>C, p.Leu301Ser) has been reported in an individual with OTC deficiency and is considered disease causing (Caldovic 2015). The leucine at codon 301 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.86). Based on available information, this variant is considered to be likely pathogenic. References: Caldovic L et al. Genotype-Phenotype Correlations in Ornithine Transcarbamylase Deficiency: A Mutation Update. J Genet Genomics. 2015 May 20;42(5):181-94. PMID: 26059767. Capistrano-Estrada S et al. Histopathological findings in a male with late-onset ornithine transcarbamylase deficiency. Pediatr Pathol. 1994 Mar-Apr;14(2):235-43. PMID: 8008687. Climent C et al. Identification of seven novel missense mutations, two splice-site mutations, two microdeletions and a polymorphic amino acid substitution in the gene for ornithine transcarbamylase (OTC) in patients with OTC deficiency. Hum Mutat. 2002 Feb;19(2):185-6. PMID: 11793483. Morel N et al. Diagnosis of ornithine transcarbamylase deficiency secondary to p.Leu301Phe mutation in an adult patient. Rev Neurol (Paris). 2012 Mar;168(3):296-7. PMID: 22340867.
Baylor Genetics RCV001228473 SCV004209066 likely pathogenic Ornithine carbamoyltransferase deficiency 2023-03-24 criteria provided, single submitter clinical testing
GenMed Metabolism Lab RCV000083598 SCV000115684 pathogenic not provided no assertion criteria provided not provided Converted during submission to Pathogenic.

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