ClinVar Miner

Submissions for variant NM_016327.3(UPB1):c.977G>A (p.Arg326Gln) (rs118163237)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000490512 SCV000267552 uncertain significance Deficiency of beta-ureidopropionase 2016-03-18 criteria provided, single submitter reference population
GeneDx RCV000514134 SCV000567006 uncertain significance not provided 2017-01-30 criteria provided, single submitter clinical testing The R326Q variant has been seen in both the homozygous and heterozygous states (along with a second UPB1 variant) in multiple individuals with beta-ureidopropionase deficiency (Nakajima et al., 2014; Shu et al., 2014). The R326Q variant is the most commonly reported variant associated with beta-ureidopropionase deficiency, with a carrier frequency of 2.8% in the Northern Chinese population and 1.8% in the Japanese population (Nakajima et al., 2014; Shu et al., 2014). Functional studies have shown that expression of beta-ureidopropionase constructs containing the R326Q variant yield little or no beta-ureidopropionase activity (Nakajima et al., 2014; van Kuilenburg et al., 2012). The R326Q variant is a semi-conservative amino acid substitution at a position that is conserved across species. However, the R326Q variant is observed in 202/8648 (2.3%) alleles from individuals of East Asian background, including four homozygous individuals, in the ExAC data set (Lek et al., 2016). We have also identified unaffected individuals who are homozygous for the R326Q variant at GeneDx. As the R326Q variant is observed in the homozygous state among unaffected individuals in the ExAC data set and at GeneDx, we interpret R326Q as a variant of uncertain significance.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000514134 SCV000610766 uncertain significance not provided 2017-06-05 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000490512 SCV000896941 uncertain significance Deficiency of beta-ureidopropionase 2018-10-31 criteria provided, single submitter clinical testing
Mendelics RCV000490512 SCV001141343 benign Deficiency of beta-ureidopropionase 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000490512 SCV001309769 likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV001449779 SCV001653055 uncertain significance not specified 2020-06-19 criteria provided, single submitter clinical testing The p.Arg326Gln variant in UPB1 has been reported in at least 12 homozygous and 6 compound heterozygous individuals with Beta-ureidopropionase deficiency and segregated with this biochemical phenotype in 1 affected individual from 1 family (van Kuilenburg 2012 PMID: 22525402, Nakajima 2014 PMID: 24526388, Shu 2104 PMID: 25236466,Lam 2015 25445412, Akiyama 2017 PMID: 27553092, Mak 2018 PMID 30109123). However, this variant has also been identified in 2.6%% (521/19954) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has also been reported in ClinVar (Variation ID 225511). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein function (Nakajima 2014 PMID: 24526388); however, these types of assays may not accurately represent biological function and homozygous individuals, though clearly deficient in Beta-ureidopropionase deficiency exhibit a wide range of phenotypes (from asymptomatic to neurological or digestive system) suggesting other factors might also be involved. In summary, the clinical significance of this variant is uncertain.

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