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

gnomAD frequency: 0.00010  dbSNP: rs138081800

Total submissions: 15

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
Labcorp Genetics (formerly Invitae), Labcorp	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
PreventionGenetics, part of Exact Sciences	RCV004751199	SCV005352526	uncertain significance	UPB1-related disorder	2024-05-16	no assertion criteria provided	clinical testing	The UPB1 c.105-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant is alternatively referred to as IVS1-2A>G in literature. It has been reported in the homozygous and compound heterozygous state in individuals with beta-ureidopropionase deficiency (van Gennip et al. 2000. PubMed ID: 11783491; van Kuilenburg et al. 2004. PubMed ID: 15385443). This variant was also reported in the homozygous in a father and daughter; however, it is unclear if the father is symptomatic (Table 1, Nakajima et al. 2014. PubMed ID: 24526388; van Kuilenburg et al. 2012. PubMed ID: 22525402). It is reported in 0.13%, including 1 homozygote, of alleles in individuals of Latino descent in gnomAD. This variant is predicted to alter splicing based on available splicing prediction programs (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751); however, the use of computer prediction programs is not equivalent to functional evidence. Taken together, while we suspect this variant could be pathogenic at this time interpret its clinical significance as uncertain due to the absence of conclusive functional and genetic evidence.