ClinVar Genomic variation as it relates to human health

Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000168, PMID:1737786). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.9>=0.6). A missense variant is a common mechanism . It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000358). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Variant summary: OAT c.722C>T (p.Pro241Leu) 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 allele was found at a frequency of 3.6e-05 in 251486 control chromosomes (gnomAD). c.722C>T has been reported in the literature as a compound heterozygous genotype in an individual affected with gyrate atrophy and in the homozygous state in an individual affected with chorioretinal dystrophy, both clinical features of Ornithine Aminotransferase Deficiency (Brody_1992, Taylor_2017). These data indicate that the variant may be associated with disease. Furthermore, examination of RNA and protein levels in fibroblasts from the compound heterozygous patient showed normal RNA expression but an undetectable level of protein, suggesting the variant impacts protein stability and/or function (Brody_1992). The following publications have been ascertained in the context of this evaluation (PMID: 1737786, 28341476). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=2)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 241 of the OAT protein (p.Pro241Leu). This variant is present in population databases (rs121965051, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of gyrate atrophy and/or Gyrate atrophy (PMID: 1737786, 28341476; Invitae). ClinVar contains an entry for this variant (Variation ID: 168). 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 OAT protein function with a positive predictive value of 80%. 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. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with gyrate atrophy of choroid and retina with or without ornithinaemia (MIM#258870). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 9 heterozygotes, 0 homozygotes). (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 aminotransferase class-III domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been identified in a pair of compound heterozygote siblings with gyrate atrophy (PMID: 11831916) and a homozygote with chorioretinal dystrophy (PMID: 28341476). In addition, it has been classified as likely pathogenic/pathogenic by diagnostic laboratories in ClinVar. (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign