Submissions for variant NM_000531.6(OTC):c.116G>A (p.Gly39Asp)

dbSNP: rs1602014500

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000810594	SCV000950812	pathogenic	Ornithine carbamoyltransferase deficiency	2023-03-02	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 39 of the OTC protein (p.Gly39Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ornithine transcarbamylase deficiency (PMID: 19138872; Invitae). ClinVar contains an entry for this variant (Variation ID: 654598). 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. This variant disrupts the p.Gly39 amino acid residue in OTC. Other variant(s) that disrupt this residue have been observed in individuals with OTC-related conditions (PMID: 9452049), which suggests that this may be a clinically significant amino acid residue.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001201208	SCV001372290	uncertain significance	not specified	2020-06-09	criteria provided, single submitter	clinical testing	Variant summary: OTC c.116G>A (p.Gly39Asp) 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 was absent in 183119 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.116G>A has been reported in the literature in an individual affected with Ornithine Transcarbamylase Deficiency (Shchelochkov_2009). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other variants in the same codon have been reported in affected individuals in the literature, suggesting the location may be important for protein function (G39C, G39V ;Calvas_1998, Zheng_2020). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV000810594	SCV002033204	uncertain significance	Ornithine carbamoyltransferase deficiency	2021-11-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003892732	SCV004708499	uncertain significance	OTC-related condition	2023-10-19	criteria provided, single submitter	clinical testing	The OTC c.116G>A variant is predicted to result in the amino acid substitution p.Gly39Asp. This variant was reported in an individual with suspected ornithine transcarbamylase (OTC) deficiency, although no additional clinical, genetic or functional evidence was provided to help establish pathogenicity (Shchelochkov et al 2009. PubMed ID: 19138872). Other variants impacting the p.Gly39 amino acid (p.Gly39Cys, p.Gly39Ala) have been reported in patients with OTC deficiency (Calvas et al. 1998. PubMed ID: 9452049; Table S2 in Makris et al. 2021. PubMed ID: 33309754), suggesting the p.Gly39 amino acid may be important for OTC function. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.