Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000274.4(OAT):c.824G>A(p.Trp275*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
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]
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 10-124403003-C-T is Pathogenic according to our data. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
This sequence change creates a premature translational stop signal (p.Trp275*) in the OAT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OAT are known to be pathogenic (PMID: 1737786, 23076989). This variant is present in population databases (rs267606924, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with OAT-related conditions. ClinVar contains an entry for this variant (Variation ID: 180). For these reasons, this variant has been classified as Pathogenic. -