Identification of novel variants in carbamoyl phosphate synthetase 1 gene and comparative pathogenicity assessments of CPS1 missense variants following ACMG/AMP-ClinGen recommendation for computational tools
Carbamoyl phosphate synthetase I (CPS1) deficiency is a rare autosomal recessive metabolic abnormality cause by dysfunctionality of CPS1 and often result in unfavorable outcome. In this study, we presented the detailed laboratory features and genetic analysis of two patients with heterozygous varian...
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Elsevier
2025-06-01
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| Series: | Molecular Genetics and Metabolism Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214426925000230 |
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| author | Fei Li Qin Cai Wei Ji Miao Xu Guoli Tian Fanyi Zeng |
| author_facet | Fei Li Qin Cai Wei Ji Miao Xu Guoli Tian Fanyi Zeng |
| author_sort | Fei Li |
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| description | Carbamoyl phosphate synthetase I (CPS1) deficiency is a rare autosomal recessive metabolic abnormality cause by dysfunctionality of CPS1 and often result in unfavorable outcome. In this study, we presented the detailed laboratory features and genetic analysis of two patients with heterozygous variants of CPS1, c.1927 A > G (p.Asn643Asp), c.2375 T > G (p.Met792Arg), c.3443 T > A (p.Met1148Lys) in patient 1; c.3784C > T (p.Arg1262Ter), c.3734 T > A (p.Leu1245His) in patient 2, respectively. c.1927 A > G (p.Asn643Asp) and c.2375 T > G (p.Met792Arg) are novel out of 5 variants and classified as variants of uncertain significance (VUS) under the guidelines of ACMG/AMP-ClinGen. Structure-based analysis of 4 missense variants indicates deleterious alterations to the protein. Since the employment of genetic testing as a clinical diagnostic tool, distinguishing pathogenic from polymorphic changes poses significant problems for geneticists. As recommendation for PP3/BP4, the computational tools for missense variant have been published, we performed a comparative evaluation for pathogenicity interpretation in our patients and in ClinVar database regarding CPS1 missense variants under the updated guidelines of ACMG/AMP-ClinGen. The application of computational tools under the ACMG/AMP-ClinGen criteria revealed an increased sensitivity for pathogenicity evaluation, from variants of uncertain significance (VUS) to likely pathogenic (LP) in previously reported cases; while for variants without clinic information in the ClinVar database, the pathogenicity assessment of VUS remained, and shows a more optimistic and reliable clinical application in molecular diagnosis. |
| format | Article |
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| institution | Kabale University |
| issn | 2214-4269 |
| language | English |
| publishDate | 2025-06-01 |
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| series | Molecular Genetics and Metabolism Reports |
| spelling | doaj-art-2ebc902dbc4c447d9436c977a76b55da2025-08-20T03:31:11ZengElsevierMolecular Genetics and Metabolism Reports2214-42692025-06-014310120810.1016/j.ymgmr.2025.101208Identification of novel variants in carbamoyl phosphate synthetase 1 gene and comparative pathogenicity assessments of CPS1 missense variants following ACMG/AMP-ClinGen recommendation for computational toolsFei Li0Qin Cai1Wei Ji2Miao Xu3Guoli Tian4Fanyi Zeng5Shanghai Children's Hospital, Shanghai Institute of Medical Genetics, Shanghai Jiao Tong University School of Medicine, Shanghai 200040, ChinaShanghai Children's Hospital, Shanghai Institute of Medical Genetics, Shanghai Jiao Tong University School of Medicine, Shanghai 200040, China; Department of Histo-Embryology, Genetics and Developmental Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, ChinaNeonatal Screening Center, Children's Hospital of Shanghai, Shanghai Jiao Tong University, Shanghai 200040, ChinaShanghai Children's Hospital, Shanghai Institute of Medical Genetics, Shanghai Jiao Tong University School of Medicine, Shanghai 200040, ChinaNeonatal Screening Center, Children's Hospital of Shanghai, Shanghai Jiao Tong University, Shanghai 200040, ChinaShanghai Children's Hospital, Shanghai Institute of Medical Genetics, Shanghai Jiao Tong University School of Medicine, Shanghai 200040, China; Department of Histo-Embryology, Genetics and Developmental Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; NHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology & Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai 200040, China; School of Pharmacy, Macau University of Science and Technology, Macau, China; Corresponding author at: Shanghai Children's Hospital, Shanghai Institute of Medical Genetics, Shanghai Jiao Tong University School of Medicine, Shanghai 200040, China.Carbamoyl phosphate synthetase I (CPS1) deficiency is a rare autosomal recessive metabolic abnormality cause by dysfunctionality of CPS1 and often result in unfavorable outcome. In this study, we presented the detailed laboratory features and genetic analysis of two patients with heterozygous variants of CPS1, c.1927 A > G (p.Asn643Asp), c.2375 T > G (p.Met792Arg), c.3443 T > A (p.Met1148Lys) in patient 1; c.3784C > T (p.Arg1262Ter), c.3734 T > A (p.Leu1245His) in patient 2, respectively. c.1927 A > G (p.Asn643Asp) and c.2375 T > G (p.Met792Arg) are novel out of 5 variants and classified as variants of uncertain significance (VUS) under the guidelines of ACMG/AMP-ClinGen. Structure-based analysis of 4 missense variants indicates deleterious alterations to the protein. Since the employment of genetic testing as a clinical diagnostic tool, distinguishing pathogenic from polymorphic changes poses significant problems for geneticists. As recommendation for PP3/BP4, the computational tools for missense variant have been published, we performed a comparative evaluation for pathogenicity interpretation in our patients and in ClinVar database regarding CPS1 missense variants under the updated guidelines of ACMG/AMP-ClinGen. The application of computational tools under the ACMG/AMP-ClinGen criteria revealed an increased sensitivity for pathogenicity evaluation, from variants of uncertain significance (VUS) to likely pathogenic (LP) in previously reported cases; while for variants without clinic information in the ClinVar database, the pathogenicity assessment of VUS remained, and shows a more optimistic and reliable clinical application in molecular diagnosis.http://www.sciencedirect.com/science/article/pii/S2214426925000230Carbamoyl phosphate synthetase I deficiencyUrea cycle disorderPathogenicity interpretationMissense variant |
| spellingShingle | Fei Li Qin Cai Wei Ji Miao Xu Guoli Tian Fanyi Zeng Identification of novel variants in carbamoyl phosphate synthetase 1 gene and comparative pathogenicity assessments of CPS1 missense variants following ACMG/AMP-ClinGen recommendation for computational tools Molecular Genetics and Metabolism Reports Carbamoyl phosphate synthetase I deficiency Urea cycle disorder Pathogenicity interpretation Missense variant |
| title | Identification of novel variants in carbamoyl phosphate synthetase 1 gene and comparative pathogenicity assessments of CPS1 missense variants following ACMG/AMP-ClinGen recommendation for computational tools |
| title_full | Identification of novel variants in carbamoyl phosphate synthetase 1 gene and comparative pathogenicity assessments of CPS1 missense variants following ACMG/AMP-ClinGen recommendation for computational tools |
| title_fullStr | Identification of novel variants in carbamoyl phosphate synthetase 1 gene and comparative pathogenicity assessments of CPS1 missense variants following ACMG/AMP-ClinGen recommendation for computational tools |
| title_full_unstemmed | Identification of novel variants in carbamoyl phosphate synthetase 1 gene and comparative pathogenicity assessments of CPS1 missense variants following ACMG/AMP-ClinGen recommendation for computational tools |
| title_short | Identification of novel variants in carbamoyl phosphate synthetase 1 gene and comparative pathogenicity assessments of CPS1 missense variants following ACMG/AMP-ClinGen recommendation for computational tools |
| title_sort | identification of novel variants in carbamoyl phosphate synthetase 1 gene and comparative pathogenicity assessments of cps1 missense variants following acmg amp clingen recommendation for computational tools |
| topic | Carbamoyl phosphate synthetase I deficiency Urea cycle disorder Pathogenicity interpretation Missense variant |
| url | http://www.sciencedirect.com/science/article/pii/S2214426925000230 |
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