Submissions for variant NM_000531.6(OTC):c.626C>T (p.Ala209Val)

dbSNP: rs72558417

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000634844	SCV000756193	pathogenic	Ornithine carbamoyltransferase deficiency	2023-05-27	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 209 of the OTC protein (p.Ala209Val). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects OTC function (PMID: 8807340, 11793468). 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: 97275). This missense change has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 8530002, 8807340, 9286441, 10070627, 12536032, 25433810). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000634844	SCV001572479	pathogenic	Ornithine carbamoyltransferase deficiency	2021-04-12	criteria provided, single submitter	clinical testing	Variant summary: OTC c.626C>T (p.Ala209Val) results in a non-conservative amino acid change located in the Aspartate/ornithine carbamoyltransferase, Asp/Orn-binding domain (IPR006131) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183102 control chromosomes. c.626C>T has been reported in the literature in multiple individuals affected with Ornithine Transcarbamylase Deficiency (e.g. Garcia-Perez_1995, Gilbert-Dussardier_1996, Popowska_1999, Kurihara_2003, Martin-Hernandez_2014, Zhou_2020). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence indicating severely reduced OTC enzyme activity in patient cells with the variant (e.g. Garcia-Perez_1995, Gilbert-Dussardier_1996). One other clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000083518	SCV001747043	pathogenic	not provided	2021-04-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000634844	SCV002033225	pathogenic	Ornithine carbamoyltransferase deficiency	2021-11-07	criteria provided, single submitter	clinical testing
GenMed Metabolism Lab	RCV000083518	SCV000115604	pathogenic	not provided		no assertion criteria provided	not provided	Converted during submission to Pathogenic.
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000634844	SCV003927817	pathogenic	Ornithine carbamoyltransferase deficiency	2023-04-01	no assertion criteria provided	clinical testing