rs200068769
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000274.4(OAT):c.1192C>T(p.Arg398Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
OAT
NM_000274.4 stop_gained
NM_000274.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 9.39
Genes affected
OAT (HGNC:8091): (ornithine aminotransferase) This gene encodes the mitochondrial enzyme ornithine aminotransferase, which is a key enzyme in the pathway that converts arginine and ornithine into the major excitatory and inhibitory neurotransmitters glutamate and GABA. Mutations that result in a deficiency of this enzyme cause the autosomal recessive eye disease Gyrate Atrophy. Alternatively spliced transcript variants encoding different isoforms have been described. Related pseudogenes have been defined on the X chromosome. [provided by RefSeq, Jan 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 17 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 10-124398070-G-A is Pathogenic according to our data. Variant chr10-124398070-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 456519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124398070-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OAT | NM_000274.4 | c.1192C>T | p.Arg398Ter | stop_gained | 10/10 | ENST00000368845.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OAT | ENST00000368845.6 | c.1192C>T | p.Arg398Ter | stop_gained | 10/10 | 1 | NM_000274.4 | P1 | |
OAT | ENST00000539214.5 | c.778C>T | p.Arg260Ter | stop_gained | 9/9 | 1 | |||
OAT | ENST00000471127.1 | n.702C>T | non_coding_transcript_exon_variant | 4/4 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152144Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250954Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135800
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461758Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727182
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Ornithine aminotransferase deficiency Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 17, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 01, 2022 | This sequence change creates a premature translational stop signal (p.Arg398*) in the OAT gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 42 amino acid(s) of the OAT protein. This variant is present in population databases (rs200068769, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with gyrate atrophy of the choroid and the retina (PMID: 7887415). ClinVar contains an entry for this variant (Variation ID: 456519). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects OAT function (PMID: 7887415, 23076989). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The stop gained variant c.1192C>T (p.Arg398Ter) in OAT gene has been reported in an individual affected with gyrate atrophy of the choroid and the retina (Michaud J et.al.,1995). Experimental studies have shown that this nonsense change leads to a drastic reduction of the OAT enzymatic activity (Doimo M et.al.,2013). This variant has been reported to the ClinVar database as Pathogenic. The p.Arg398Ter variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.000797% is reported in gnomAD. The nucleotide change in OAT is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 18, 2020 | - - |
Hyperornithinemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 28, 2022 | Variant summary: OAT c.1192C>T (p.Arg398X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein. Truncations downstream of this position have been classified as pathogenic in ClinVar and is associated with Gyrate atrophy in HGMD. The variant allele was found at a frequency of 8e-06 in 250954 control chromosomes (gnomAD). c.1192C>T has been reported in the literature in individuals affected with Ornithine Aminotransferase Deficiency (examples: Michaud_1995 and Cleary_2005). These data indicate that the variant is associated with disease. Multiple publications have provided experimental evidence that this variant abolishes the protein function (example: Doimo_2012 and Cleary_2005). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at