ClinVar Genomic variation as it relates to human health
NM_000274.4(OAT):c.722C>T (p.Pro241Leu)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000274.4(OAT):c.722C>T (p.Pro241Leu)
Variation ID: 168 Accession: VCV000000168.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q26.13 10: 124403847 (GRCh38) [ NCBI UCSC ] 10: 126092416 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 26, 2017 Jul 23, 2024 Dec 21, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000274.4:c.722C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000265.1:p.Pro241Leu missense NM_001171814.2:c.308C>T NP_001165285.1:p.Pro103Leu missense NM_001322965.2:c.722C>T NP_001309894.1:p.Pro241Leu missense NM_001322966.2:c.722C>T NP_001309895.1:p.Pro241Leu missense NM_001322967.2:c.722C>T NP_001309896.1:p.Pro241Leu missense NM_001322968.2:c.722C>T NP_001309897.1:p.Pro241Leu missense NM_001322969.2:c.722C>T NP_001309898.1:p.Pro241Leu missense NM_001322970.2:c.722C>T NP_001309899.1:p.Pro241Leu missense NM_001322971.2:c.401C>T NP_001309900.1:p.Pro134Leu missense NM_001322974.2:c.122C>T NP_001309903.1:p.Pro41Leu missense NC_000010.11:g.124403847G>A NC_000010.10:g.126092416G>A NG_008861.1:g.20104C>T NG_075868.1:g.408G>A LRG_685:g.20104C>T LRG_685t1:c.722C>T LRG_685p1:p.Pro241Leu P04181:p.Pro241Leu - Protein change
- P241L, P103L, P134L, P41L
- Other names
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- Canonical SPDI
- NC_000010.11:124403846:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00004
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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LOC121815974 | - | - | - | GRCh38 | - | 76 |
OAT | - | - |
GRCh38 GRCh37 |
587 | 700 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Dec 21, 2023 | RCV000000191.19 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 16, 2023 | RCV003234882.8 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Mar 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Ornithine aminotransferase deficiency
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002318565.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
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). … (more)
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. (less)
Clinical Features:
Aggressive behavior (present) , Intellectual disability (present) , Abnormal facial shape (present) , Hyperornithinemia (present)
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Likely pathogenic
(May 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hyperornithinemia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003934421.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Nov 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Ornithine aminotransferase deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000626801.4
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
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). … (more)
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. (less)
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Pathogenic
(Dec 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Ornithine aminotransferase deficiency
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005085993.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
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 … (more)
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 (less)
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Likely pathogenic
(Jun 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Ornithine aminotransferase deficiency
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004208938.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jun 01, 1992)
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no assertion criteria provided
Method: literature only
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GYRATE ATROPHY OF CHOROID AND RETINA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000020334.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 04, 2018 |
Comment on evidence:
Using SSCP analysis, Michaud et al. (1992) demonstrated a pro241-to-leu (P241L) mutation resulting from a C-to-T transition at nucleotide 722 of the OAT mRNA in … (more)
Using SSCP analysis, Michaud et al. (1992) demonstrated a pro241-to-leu (P241L) mutation resulting from a C-to-T transition at nucleotide 722 of the OAT mRNA in a patient with gyrate atrophy of the choroid and retina (GACR; 258870). (less)
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Likely pathogenic
(Jan 28, 2021)
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no assertion criteria provided
Method: clinical testing
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Gyrate atrophy
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002090789.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Panel-Based Clinical Genetic Testing in 85 Children with Inherited Retinal Disease. | Taylor RL | Ophthalmology | 2017 | PMID: 28341476 |
Gyrate atrophy of the choroid and retina: further experience with long-term reduction of ornithine levels in children. | Kaiser-Kupfer MI | Archives of ophthalmology (Chicago, Ill. : 1960) | 2002 | PMID: 11831916 |
Ornithine delta-aminotransferase mutations in gyrate atrophy. Allelic heterogeneity and functional consequences. | Brody LC | The Journal of biological chemistry | 1992 | PMID: 1737786 |
Strand-separating conformational polymorphism analysis: efficacy of detection of point mutations in the human ornithine delta-aminotransferase gene. | Michaud J | Genomics | 1992 | PMID: 1612597 |
Text-mined citations for rs121965051 ...
HelpRecord last updated Aug 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.