Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

OAT : gyrate atrophy

HGNC:8091 | MONDO_0009796
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Aminoacidopathy
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 4
Doimo M et al. 2013 Jan (PMID:23076989); Katagiri S et al. 2014 Apr (PMID:24429551); Mashima Y et al. 1992 Jul (PMID:1609808);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 6
Ramesh V et al. 1988 Jun (PMID:3375240); Doimo M et al. 2013 Jan (PMID:23076989); Mitchell GA et al. 1988 Feb (PMID:3339136); Mitchell GA et al. 1989 Jan (PMID:2492100);
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
Juncosa JI et al. 2013 Sep 15 (PMID:23747282);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Bernstein SL et al. 1998 Nov 5 (PMID:9815288);
Functional Alteration Patient cells 1 0 - 2 2 1
Heinänen K et al. 1998 Sep (PMID:9727717);
Non-patient cells 0.5 0 - 1 1 0.5
Montioli R et al. 2018 Nov (PMID:30251682);
Models Non-human model organism 2 0 - 4 4 3 7 4
Wang T et al. 1995 Oct (PMID:7550347); Wang T et al. 2000 Feb 1 (PMID:10655512); Bisaillon JJ et al. 2014 (PMID:25264521);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 6 18 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The relationship between OAT and gyrate atrophy of the choroid and retina, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of July 2, 2019. OAT encodes ornithine aminotransferase, a mitochondrial enzyme that catalyzes the pyridoxal 5′-phosphate-dependent transformation of L-ornithine to L-glutamate 5-semialdehyde, which spontaneously forms pyrroline-5-carboxylate. Variants in OAT causing gyrate atrophy were first reported in 1988 (Ramesh et al, PMID 3375240; Mitchel et al, PMID 3339136). Hyperornithininemia is a consistent biochemical finding in these patients. Data from 10 patients with 13 unique variants (missense, nonsense, frameshift, splicing, large deletion) from 6 publications were curated (Mitchel et al, 1988, PMID 3339136; Ramesh et al, 1988, PMID 3375240; Mitchel et al, 1989, PMID 2492100; Mashima et al, 1992, PMID 1609808; Doimo et al, 2013, PMID 23076989; Katagiri et al, 2014, PMID 24429551). Additional cases are available in the literature but the maximum score for genetic evidence (12 points) has been reached. Of note, rare individuals with OAT deficiency have been reported who presented with hyperammonemia and low ornithine in the neonatal period, later developing hyperornithinemia (Cleary et al, 2005, PMID 16151897; Zubarioglu et al, 2016; PMID 27037922). While these individuals had no signs of gyrate atrophy, it is possible that it may develop later in life. The relationship between OAT and gyrate atrophy is supported by extensive experimental evidence including the biochemical function of ornithine aminotransferase, which is consistent with the biochemical features of the disease (Juncosa et al, 2103, PMID 23747282), expression of OAT in the retina (Bernstein et al, 1988, PMID 9815288), functional studies in patient and non-patient cells (Heinänen et al, 1988, PMID 9727717; Montioli et al, 2018, PMID 30251682), as well as the phenotype in naturally-occurring and knock-out mouse models (Bisaillon et al, 2014, PMID 25264521; Wang et al, 1995, PMID 7550347; Wang et al, 2000, PMID 10655512). In summary, OAT is definitively associated with gyrate atrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel.