Submissions for variant NM_000531.6(OTC):c.118C>T (p.Arg40Cys)

gnomAD frequency: 0.00005  dbSNP: rs72554307

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000011760	SCV000756189	pathogenic	Ornithine carbamoyltransferase deficiency	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 40 of the OTC protein (p.Arg40Cys). This variant is present in population databases (rs72554307, gnomAD 0.003%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with clinical features of ornithine transcarbamylase deficiency (PMID: 7860066, 11260212, 23209112; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11013). 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%. This variant disrupts the p.Arg40 amino acid residue in OTC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7951259, 19893582, 25026867). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000011760	SCV000893833	likely pathogenic	Ornithine carbamoyltransferase deficiency	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000011760	SCV001372246	pathogenic	Ornithine carbamoyltransferase deficiency	2020-06-15	criteria provided, single submitter	clinical testing	Variant summary: OTC c.118C>T (p.Arg40Cys) results in a non-conservative amino acid change located in the Aspartate/ornithine carbamoyl transferase, carbamoyl-P binding domain (IPR006132) of 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 1.1e-05 in 183119 control chromosomes. c.118C>T has been reported in the literature in individuals affected with later onset Ornithine Transcarbamylase Deficiency and has subsequently cited by others (example, Oppliger Leibundgut_1995, Ploechl_2001, Thurlow_2010, Cavicchi_2014, Caldovic_2015, Ihara_2012). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal OTC activity (Oppliger Leibundgut_1995). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Lastly, another variant at this codon, p.Arg40His has been reported in patients with OTC deficiency supporting the functional relevance of this residue. Based on the evidence outlined above, the variant was classified as pathogenic for fatal late-onset OTC deficiency in boys.
Genome-Nilou Lab	RCV000011760	SCV002033212	pathogenic	Ornithine carbamoyltransferase deficiency	2021-11-07	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000011760	SCV002768001	pathogenic	Ornithine carbamoyltransferase deficiency	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ornithine transcarbamylase (OTC) deficiency (MIM#311250). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (2 heterozygotes, 0 homozygotes, 1 hemizygote). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated aspartate/ornithine carbamoyltransferase, carbamoyl-P binding domain (Pfam). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. p.(Arg40Leu) has previously been reported in an adult male OTC deficiency patient (PMID: 25026867). In addition, p.(Arg40His) has also been reported in at least 10 OTC deficiency patients and has been suggested to result in a milder phenotype then p.(Arg40Cys) (ClinVar, PMID: 25026867; 11260212; 32995020; 19893582). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least eight individuals and is consistently reported as a fatal late childhood/adulthood onset form of ornithine transcarbamylase deficiency (ClinVar; PMID: 7860066; 20406775; 11260212; 27738433). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx	RCV000083332	SCV003805345	likely pathogenic	not provided	2023-02-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23209112, 28324312, 8863155, 9143919, 20406775, 21070677, 11793468, 11260212, 7860066, 8364586, 25026867, 34014569, 35046116)
OMIM	RCV000011760	SCV000031992	pathogenic	Ornithine carbamoyltransferase deficiency	2001-02-01	no assertion criteria provided	literature only
GenMed Metabolism Lab	RCV000083332	SCV000115418	pathogenic	not provided		no assertion criteria provided	not provided	Converted during submission to Pathogenic.
Natera, Inc.	RCV000011760	SCV001458515	likely pathogenic	Ornithine carbamoyltransferase deficiency	2020-09-16	no assertion criteria provided	clinical testing