ClinVar Genomic variation as it relates to human health

PS4, PP3, PM2_SUP

PP1, PP4, PM2, PM5, PS3

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 40 of the OTC protein (p.Arg40His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ornithine transcarbamylase deficiency (PMID: 7951259, 19893582, 25026867). ClinVar contains an entry for this variant (Variation ID: 11014). 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%. Experimental studies have shown that this missense change affects OTC function (PMID: 11102556). 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: 7860066, 7951259, 19893582, 23209112, 25026867; Invitae). 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.

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 disease. (I) 0115 - Variants in this gene are known to have variable expressivity. In males, the phenotypic spectrum can range from lethal neonatal onset to milder forms in late childhood or adulthood while in heterozygous females, the phenotypic spectrum can range from asymptomatic to having recurrent hyperammonemia and/or neurologic impairment depending on the pattern of X-chromosome inactivation in the liver (OMIM, GeneReviews). In addition, individuals with pathogenic variants associated with mild, late-onset disease may experience severe hyperammonemia depending on exposure to strong environmental stressors (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (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) (p.(Arg40Cys): 2 heterozygotes, 1 hemizygote, 0 homozygote). (I) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0600 - Variant is located in the annotated OTCace_N domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories (ClinVar). While this variant is commonly associated with milder, later-onset ornithine transcarbamylase deficiency, it has been reported in the context of severe early-onset disease, including one 7-day-old infant (PMIDs: 19893582, 25958381, 32934962). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Variant summary: OTC c.119G>A (p.Arg40His) 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 183119 control chromosomes (gnomAD). c.119G>A has been reported in the literature in multiple individuals affected with ornithine transcarbamylase deficiency and several of these individuals had a late-onset presentation (example: Toquet_2020 , Harada_2006 ). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.118C>T, p.Arg40Cys), supporting the critical relevance of codon 40 to OTC protein function. In vitro and in vivo functional studies reveal reduced activity of the variant (Augustin_2000, Harada_2006). The following publications have been ascertained in the context of this evaluation (PMID: 34014557, 16635166, 11102556). ClinVar contains an entry for this variant (Variation ID: 11014). Based on the evidence outlined above, the variant was classified as pathogenic.

Not observed at significant frequency in large population cohorts (gnomAD); 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: 9175746, 34014569, 32995020, 32934962, 7951259, 30449781, 28324312, 31447099, 21070677, 33309754, 33272297, 33763331, 36854409, 19893582, 37146589, 17334707, 11260212, 11768581, 8863155, 11102556, 34014557, 9048915, 25026867)

The c.119G>A (p.Arg40His) variant was previously detected in several patients and families with OTC deficiency, males and females [PMID 21070677, 2095337, 7951259]. Among them, a heterozygous female became symptomatic with hyperammenomia and acute decompensation at 13 years of age [PMID 21070677]. Additionally, a family with a hemizygous male and heterozygous sister also became symptomatic in their teenage years [PMID 2095337]. Their mother, also heterozygous, was asymptomatic but showed small orotic aciduria after protein loading. This variant has also been observed in our internal database in a 10 y/o patient with recent symptoms of OTC deficiency. Another change at the same amino acid location (p.Arg40Cys) has been reported but is considered a variant of unknown significance by our classification criteria at this time. This variant is not conserved in all mammals. Computer based prediction softwares yield discordant results regarding the pathogenicity of this change. This variant has not been observed in the ExAC database but has been detected in multiple patients and it is thus classified as pathogenic.

Converted during submission to Pathogenic.