ClinVar Miner

Submissions for variant NM_016327.3(UPB1):c.105-2A>G

gnomAD frequency: 0.00010  dbSNP: rs138081800
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000004363 SCV000743132 pathogenic Deficiency of beta-ureidopropionase 2017-07-28 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000004363 SCV000744134 likely pathogenic Deficiency of beta-ureidopropionase 2017-11-24 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000004363 SCV000893585 pathogenic Deficiency of beta-ureidopropionase 2018-10-31 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000004363 SCV001251680 pathogenic Deficiency of beta-ureidopropionase 2024-01-09 criteria provided, single submitter clinical testing
Elsea Laboratory, Baylor College of Medicine RCV000004363 SCV001424294 pathogenic Deficiency of beta-ureidopropionase 2020-04-01 criteria provided, single submitter clinical testing
Invitae RCV001384579 SCV001584122 pathogenic not provided 2023-09-29 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 1 of the UPB1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in UPB1 are known to be pathogenic (PMID: 15385443, 22525402). This variant is present in population databases (rs138081800, gnomAD 0.1%). Disruption of this splice site has been observed in individuals with ureidopropionase deficiency (PMID: 11783491, 15385443, 22525402, 24526388). ClinVar contains an entry for this variant (Variation ID: 4147). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000004363 SCV002020825 pathogenic Deficiency of beta-ureidopropionase 2023-02-07 criteria provided, single submitter clinical testing
GeneDx RCV001384579 SCV002031024 pathogenic not provided 2022-08-26 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 15385443, 11783491, 31980526, 32552793, 34426522, 31589614)
Ambry Genetics RCV002512751 SCV003681678 pathogenic Inborn genetic diseases 2022-01-13 criteria provided, single submitter clinical testing The c.105-2A>G intronic variant results from an A to G substitution two nucleotides before coding exon 2 of the UPB1 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from gnomAD, the G allele has an overall frequency of 0.04% (100/282684) total alleles studied. The highest observed frequency was 0.13% (46/35436) of Latino alleles. This variant has been identified in the homozygous state in three individuals (two siblings) and confirmed in trans with a canonical splice variant in one individual with beta-ureidopropionase deficiency (van Kuilenburg, 2004; van Kuilenburg, 2012). Based on the available evidence, this alteration is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000004363 SCV003928434 pathogenic Deficiency of beta-ureidopropionase 2023-04-05 criteria provided, single submitter clinical testing Variant summary: UPB1 c.105-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' splicing acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00038 in 251290 control chromosomes in the gnomAD database, including 1 homozygote. This frequency does not allow conclusions about variant significance. c.105-2A>G has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with Deficiency Of Beta-Ureidopropionase (example, van Gennip_2000, van Kuilenburg_2004, Nakajima_2014, Righetti_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (P/LP, n=9; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center RCV000004363 SCV004012849 pathogenic Deficiency of beta-ureidopropionase 2023-07-12 criteria provided, single submitter clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000004363 SCV004805118 likely pathogenic Deficiency of beta-ureidopropionase 2024-03-17 criteria provided, single submitter research
OMIM RCV000004363 SCV000024534 pathogenic Deficiency of beta-ureidopropionase 2004-11-15 no assertion criteria provided literature only
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City RCV000004363 SCV001469272 pathogenic Deficiency of beta-ureidopropionase 2020-08-07 no assertion criteria provided clinical testing

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