Submissions for variant NM_000531.6(OTC):c.76C>T (p.Arg26Trp)

gnomAD frequency: 0.00002  dbSNP: rs1057515879

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000363211	SCV000482289	uncertain significance	Ornithine carbamoyltransferase deficiency	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589394	SCV000697262	uncertain significance	not provided	2016-12-09	criteria provided, single submitter	clinical testing	Variant summary: The OTC c.76C>T (p.Arg26Trp) variant involves the alteration of a non-conserved nucleotide. This variant is located within the carbamoyl-P binding domain. 3/5 in silico tools predict a benign outcome for this variant, however this particular alteration has yet to be functionally assessed. . This variant is absent from control population dataset of ExAC. The variant was identified in a pt undergoing WES due to clinical presentations nonspecific and unrelated to ornithine transcabamylase deficiency, although, pt did report episodes of memory loss. The variant was inherited from reportedly unaffected father. Another alteration of the same codon, p.R26Q has been reported in several affected individuals with biochemically confirmed OTC-deficiency. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, but was cited as VUS by a reputable database/clinical diagnostic laboratory. The p.R26W may represent either a late-onset mild mutation or rare functional variant. At this point, there is no sufficient evidence to classify c.76C>T with confidence. Taken together, this variant is classified as VUS.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000363211	SCV000756192	uncertain significance	Ornithine carbamoyltransferase deficiency	2024-06-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 26 of the OTC protein (p.Arg26Trp). This variant is present in population databases (no rsID available, gnomAD 0.009%). This missense change has been observed in individual(s) with a positive newborn screening result for OTC-related disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 368257). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The tryptophan amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000363211	SCV001251791	uncertain significance	Ornithine carbamoyltransferase deficiency	2020-05-03	criteria provided, single submitter	clinical testing
Pars Genome Lab	RCV000363211	SCV001736773	uncertain significance	Ornithine carbamoyltransferase deficiency	2021-05-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000363211	SCV002033203	uncertain significance	Ornithine carbamoyltransferase deficiency	2021-11-07	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000363211	SCV001458513	uncertain significance	Ornithine carbamoyltransferase deficiency	2020-09-16	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000589394	SCV001797708	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000589394	SCV001969300	likely benign	not provided		no assertion criteria provided	clinical testing