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Variant Classification Rules for Ornithine Transca ...
Variant Classification Rules for Ornithine Transcarbamylase, N-Acetylglutamate Synthase, and Carbamylphosphate Synthetase 1
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The document discusses variant classification rules for three key enzymes involved in the urea cycle: Ornithine Transcarbamylase (OTC), N-Acetylglutamate Synthase (NAGS), and Carbamylphosphate Synthetase 1 (CPS1). Urea cycle disorders (UCDs) are genetic conditions affecting the metabolism of ammonia, leading to severe consequences if left untreated. OTC, NAGS, and CPS1 deficiencies are particularly critical and often present with severe symptoms. The document outlines gene-specific criteria for classifying variants in these enzymes, considering factors such as variant type, allele frequency, functional assays, and phenotype.<br /><br />The ClinGen Urea Cycle Disorders Variant Curation Expert Panel was formed to evaluate and classify genomic variants in urea cycle genes. Criteria were established based on disease severity and prevalence, categorized into tiers for proximal urea cycle genes, distal urea cycle genes, and transporters. The rules consider factors like enzyme activity, biochemical testing, and genetic segregation for variant classification.<br /><br />Additionally, various gene-specific criteria were specified for OTC, NAGS, and CPS1 variants, outlining requirements related to initiation codons, amino acid positions, enzyme activity, and allele frequency. The results section confirms criteria that were not modified and highlights the inclusion of validated rules for OTC, NAGS, and CPS1 variants. The document mentions plans for further validation and acknowledges funding from NIH grants.<br /><br />Overall, the document provides detailed guidelines for classifying variants in key enzymes related to the urea cycle, aiming to improve the understanding and interpretation of genetic variations associated with urea cycle disorders.
Keywords
Urea cycle disorders
Ornithine Transcarbamylase
N-Acetylglutamate Synthase
Carbamylphosphate Synthetase 1
Genomic variants
Variant classification rules
Enzyme activity
Allele frequency
Biochemical testing
Genetic variations
Ljubica Caldovic (lcaldovic@childrensnational.org)
© 2024 American College of Medical Genetics and Genomics. All rights reserved.
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