Submissions for variant NM_016327.3(UPB1):c.917-1G>A

gnomAD frequency: 0.00169  dbSNP: rs143493067

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514100	SCV000610809	pathogenic	not provided	2017-05-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763075	SCV000893586	pathogenic	Deficiency of beta-ureidopropionase	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000514100	SCV001249407	pathogenic	not provided	2019-08-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000763075	SCV001306777	benign	Deficiency of beta-ureidopropionase	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Elsea Laboratory, Baylor College of Medicine	RCV000763075	SCV001424297	pathogenic	Deficiency of beta-ureidopropionase	2020-04-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000763075	SCV001527900	pathogenic	Deficiency of beta-ureidopropionase	2018-06-07	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Labcorp Genetics (formerly Invitae), Labcorp	RCV000514100	SCV001589361	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 8 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 (rs143493067, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individuals with beta-ureidopropionase deficiency (PMID: 11783491, 15385443, 24526388). This variant is also known as IVS8-1G>A. ClinVar contains an entry for this variant (Variation ID: 445946). 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.
GeneDx	RCV000514100	SCV001804494	pathogenic	not provided	2022-05-04	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 11783491, 15385443, 31589614, 30487145, 34426522, 33789662, 24526388, 30608453)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000514100	SCV002011602	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000763075	SCV002021600	pathogenic	Deficiency of beta-ureidopropionase	2023-09-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000763075	SCV002041752	pathogenic	Deficiency of beta-ureidopropionase	2021-11-12	criteria provided, single submitter	clinical testing	Variant summary: UPB1 c.917-1G>A alters a conserved nucleotide 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' splice acceptor site. Three predict the variant strengthens a cryptic exonic alternate 3' acceptor site. However, these predictions have yet to be unequivocally confirmed by functional studies. One publication reported a transcript with deletion of exon 6 presumably leading to a frameshift and probably a nonfunctional transcript. However, a transcript lacking exon 9 was not detected in this study (Kuilenburg_2006). Furthermore, the authors did not present primary data supporting their reported outcome. The variant allele was found at a frequency of 0.0018 in 251448 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in UPB1 causing Deficiency Of Beta-Ureidopropionase allowing no conclusion about variant significance. c.917-1G>A has been reported in the literature in individuals affected with Deficiency Of Beta-Ureidopropionase (example, Kuilenburg_2004, Kuilenburg_2012, Fang_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic, n=3, Benign, n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002528233	SCV003734748	pathogenic	Inborn genetic diseases	2022-02-11	criteria provided, single submitter	clinical testing	The c.917-1G>A intronic variant results from a G to A substitution one nucleotide before coding exon 9 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 A allele has an overall frequency of 0.18% (506/282852) total alleles studied. The highest observed frequency was 0.37% (38/10368) of Ashkenazi Jewish alleles. This mutation has been identified in the homozygous and compound heterozygous state in individuals with beta-ureidopropionase deficiency (van Kuilenburg, 2004; van Kuilenburg, 2012). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000763075	SCV004848625	likely pathogenic	Deficiency of beta-ureidopropionase	2022-03-02	criteria provided, single submitter	clinical testing	The c.917-1G>A variant in UPB1 has been reported in a homozygote infant who suffered sudden unexplained death (Schon 2021 PMID: 33789662) and in at least 1 homozygous and 2 compound-heterozygous individuals affected with beta-ureidopropionase deficiency (Van Kuilenburg 2004 PMID: 15385443, Fang 2019 PMID: 30608453, Nakajima 2014 PMID: 24526388). In one of these individuals this variant was found in the compound heterozygous state with another loss-of-function variant affecting a canonical splice site that is classified as pathogenic by multiple submitters in ClinVar (Variation ID: 4147). The variant has been identified in 0.366% (38/10368) of Ashkenazi Jewish chromosomes and 0.277% (358/129172), including one homozygote, of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). These frequencies, however, are low enough to be consistent with a recessive carrier frequency for a disorder exhibiting low penetrance/variable expressivity as has been reported for beta-ureidopropionase deficiency (van Kuilenburg 2004 PMID: 15385443). This variant has also been reported in ClinVar (Variation ID 445946). It occurs in the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the UPB1 gene is an established disease mechanism in autosomal recessive beta-ureidopropionase deficiency. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive beta-ureidopropionase deficiency. ACMG/AMP Criteria applied: PVS1, PM3.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000763075	SCV005016589	likely pathogenic	Deficiency of beta-ureidopropionase	2024-03-14	criteria provided, single submitter	clinical testing
OMIM	RCV000763075	SCV000024535	pathogenic	Deficiency of beta-ureidopropionase	2004-11-15	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000514100	SCV001743712	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000514100	SCV001970931	likely pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003424067	SCV004107902	pathogenic	UPB1-related disorder	2024-01-28	no assertion criteria provided	clinical testing	The UPB1 c.917-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported previously in the compound heterozygous and homozygous state in multiple patients as causative for β-ureidopropionase deficiency (van Kuilenburg et al. 2004. PubMed ID: 15385443; van Kuilenburg et al. 2012. PubMed ID: 22525402; Fang et al. 2019. PubMed ID: 30608453; OMIM #613161). Specifically, the individual homozygous for this variant presented with a prolonged seizure event (status epilepticus) following a hospital visit for cyanosis (van Kuilenburg et al. 2004, PubMed ID: 15385443). This variant is reported in 0.37% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At PreventionGenetics, we have observed this variant in the homozygous state in an individual with biochemically confirmed β-ureidopropionase deficiency. Taken together, we classify this variant as pathogenic.