rs121965051
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000274.4(OAT):c.722C>T(p.Pro241Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,980 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P241P) has been classified as Likely benign.
Frequency
Consequence
NM_000274.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OAT | NM_000274.4 | c.722C>T | p.Pro241Leu | missense_variant | 6/10 | ENST00000368845.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OAT | ENST00000368845.6 | c.722C>T | p.Pro241Leu | missense_variant | 6/10 | 1 | NM_000274.4 | P1 | |
OAT | ENST00000539214.5 | c.308C>T | p.Pro103Leu | missense_variant | 5/9 | 1 | |||
OAT | ENST00000467675.5 | n.523C>T | non_coding_transcript_exon_variant | 5/7 | 5 | ||||
OAT | ENST00000483711.1 | n.568C>T | non_coding_transcript_exon_variant | 2/2 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251486Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135920
GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461840Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21AN XY: 727230
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74310
ClinVar
Submissions by phenotype
Ornithine aminotransferase deficiency Pathogenic:6
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 28, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 20, 2023 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 17, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Mar 22, 2022 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Dec 21, 2023 | 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 - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 1992 | - - |
Hyperornithinemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 16, 2023 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at