Submissions for variant NM_000531.6(OTC):c.374C>T (p.Thr125Met)

gnomAD frequency: 0.00001  dbSNP: rs72554356

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CSER _CC_NCGL, University of Washington	RCV000148721	SCV000190453	uncertain significance	Hyperammonemia	2014-06-01	criteria provided, single submitter	research	Low GERP score may suggest that this variant may belong in a lower pathogenicity class
CeGaT Center for Human Genetics Tuebingen	RCV000083408	SCV000780968	uncertain significance	not provided	2018-02-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000702655	SCV000831517	uncertain significance	Ornithine carbamoyltransferase deficiency	2022-07-06	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 125 of the OTC protein (p.Thr125Met). This variant is present in population databases (rs72554356, gnomAD 0.008%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with OTC deficiency (PMID: 8807340). ClinVar contains an entry for this variant (Variation ID: 97175). 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 not expected to disrupt OTC protein function. Experimental studies have shown that this missense change affects OTC function (PMID: 17613537). 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.
GeneDx	RCV000083408	SCV001829538	uncertain significance	not provided	2020-11-11	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that the T125M variant has reduced activity compared to wild type (Suriano et al., 2007); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in an individual with OTC deficiency by enzyme results, however full sequencing of OTC gene was not performed (Gilbert-Dussardier et al., 1996); This variant is associated with the following publications: (PMID: 17613537, 25637381, 27703146, 8807340, 28324312, 9452049)
Genome-Nilou Lab	RCV000702655	SCV002033207	uncertain significance	Ornithine carbamoyltransferase deficiency	2021-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323392	SCV004028789	uncertain significance	not specified	2023-07-28	criteria provided, single submitter	clinical testing	Variant summary: OTC c.374C>T (p.Thr125Met) results in a non-conservative amino acid change located in the carbamoyl-P binding domain (IPR006132) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 182605 control chromosomes, including 2 hemizygotes, suggesting the variant may be benign. c.374C>T has been reported in the literature as a hemizygous genotype in at least one individual affected with neonatal onset Ornithine Transcarbamylase Deficiency who also had two unaffected female relatives who carried the variant, however X-inactivation pattern was not reported in these individuals (e.g. Gilbert-Dussardier_1996, Gobin-Limballe_2021). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant results in little to no enzyme activity compared to the WT protein (Suriano_2007). The following publications have been ascertained in the context of this evaluation (PMID: 25637381, 8807340, 34014569, 17613537). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000702655	SCV004047963	uncertain significance	Ornithine carbamoyltransferase deficiency		criteria provided, single submitter	clinical testing	The missense variant c.374C>T (p.Thr125Met) in OTC has been submitted to ClinVar as a Variant of Uncertain Significance. This variant has been observed in an individual affected with OTC deficiency (Gilbert-Dussardier B et al). Experimental studies have shown that this missense change causes lack of OTC enzymatic activity in vitro (Suriano G et al) This p.Thr125Met variant has allele frequency of 0.001095% in the gnomAD and novel (not in any individuals) in 1000 genome database. The amino acid Thr at position 125 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. For these reasons, this variant has been classified as Uncertain Significance (VUS).
GenMed Metabolism Lab	RCV000083408	SCV000115494	pathogenic	not provided		no assertion criteria provided	not provided	Converted during submission to Pathogenic.
Natera, Inc.	RCV000702655	SCV002087167	uncertain significance	Ornithine carbamoyltransferase deficiency	2020-12-10	no assertion criteria provided	clinical testing