Submissions for variant NM_000531.6(OTC):c.1061T>G (p.Phe354Cys)

gnomAD frequency: 0.00001  dbSNP: rs72558495

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV001095686	SCV001251476	likely pathogenic	Ornithine carbamoyltransferase deficiency		criteria provided, single submitter	research	The OTC c.1061T>G (p.F354C) variant was previously reported in mild ornithine transcarbamylase deficiency (PMID: 8857803; 16786505).
GeneDx	RCV000083329	SCV001825855	likely pathogenic	not provided	2024-08-22	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9266388, 8857803, 28324312, 16786505, 32853555, 37146589)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001095686	SCV002766071	likely pathogenic	Ornithine carbamoyltransferase deficiency	2022-11-15	criteria provided, single submitter	clinical testing	Variant summary: OTC c.1061T>G (p.Phe354Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 182812 control chromosomes. c.1061T>G has been reported in the literature in individuals affected with Ornithine Transcarbamylase Deficiency. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in less than 2% of normal activity. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001095686	SCV003445216	pathogenic	Ornithine carbamoyltransferase deficiency	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 354 of the OTC protein (p.Phe354Cys). This variant is present in population databases (rs72558495, gnomAD 0.001%). This missense change has been observed in individuals with ornithine transcarbamylase deficiency (PMID: 9266388, 10869432). ClinVar contains an entry for this variant (Variation ID: 97104). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001095686	SCV004209063	pathogenic	Ornithine carbamoyltransferase deficiency	2023-09-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001095686	SCV004833181	uncertain significance	Ornithine carbamoyltransferase deficiency	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with cysteine at the last amino acid codon 354 of the OTC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a 13-year old boy diagnosed with late-onset ornithine transcarbamylase deficiency based on hyperammonemia and 1.8% residual OTC enzyme activity detected in his liver tissue frozen at autopsy (PMID: 8857803). This variant has been observed in a male with first presentation of hyperammonemia at age 14, as well as in his 55-year old, asymptomatic grandfather (PMID: 10946359). OTC enzyme activity was not determined in the proband. This variant has also been observed in a newborn girl diagnosed with phenylketonuria and unaffected with symptoms of ornithine transcarbamylase deficiency (PMID: 32853555). Her grandfather and younger male sibling were unaffected carriers of this variant. This variant has been identified in 1/182812 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GenMed Metabolism Lab	RCV000083329	SCV000115415	pathogenic	not provided		no assertion criteria provided	not provided	Converted during submission to Pathogenic.
Natera, Inc.	RCV001095686	SCV002087188	likely pathogenic	Ornithine carbamoyltransferase deficiency	2017-08-03	no assertion criteria provided	clinical testing