ClinVar Genomic variation as it relates to human health

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

The c.622G>A (p.A208T) alteration is located in exon 6 (coding exon 6) of the OTC gene. This alteration results from a G to A substitution at nucleotide position 622, causing the alanine (A) at amino acid position 208 to be replaced by a threonine (T). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple individuals with ornithine transcarbamylase deficiency and segregates with disease in multiple families (van Diggelen, 1996; Schultz, 2000; Cavicchi, 2014; Martín-Hernández, 2014; Gascon-Bayarri, 2015; Sánchez, 2017; Silvera-Ruiz, 2019; Lu, 2020). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

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 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 alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a minor amino acid change. (SP) 0600 - Variant is located in the annotated Aspartate/ornithine carbamoyltransferase, Asp/Orn binding domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individual and has been reported more than five times as pathogenic in ClinVar. In the literature, this variant is well-reported in patients with ornithine transcarbamylase deficiency and is typically asscoiated with late-onset disease. However, it has also been reported to cause severe disease in childhood (LOVD, PMID: 9007316, 28261508, 34014557). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Variant summary: OTC c.622G>A (p.Ala208Thr) results in a non-conservative amino acid change located in the Aspartate/ornithine carbamoyltransferase, Asp/Orn-binding domain (IPR006131) of 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 183108 control chromosomes. c.622G>A has been reported in the literature in multiple individuals affected with late-onset Ornithine Transcarbamylase Deficiency (e.g. Toquet_2021, van Diggelen_1996, Ausems_1997). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 9028466, 34014557, 9007316). ClinVar contains an entry for this variant (Variation ID: 97274). Based on the evidence outlined above, the variant was classified as pathogenic.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18071043, 34014569, 34014557, 25026867, 26819360, 28261508, 17437397, 9028466, 28597413, 28324312, 33309754, 33272297, 9007316)

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 208 of the OTC protein (p.Ala208Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 9007316, 9028466, 10799432, 25949836, 26819360). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 97274). 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%. For these reasons, this variant has been classified as Pathogenic.

ACMG Criteria: PS4, PM1, PM2_P, PP1, PP3, PP5; Variant was found in hemizygous state

Converted during submission to Pathogenic.