ClinVar Genomic variation as it relates to human health

The UGT1A1 c.674T>G (p.Val225Gly) variant is reported in a total of six individuals with Crigler-Najjar syndrome, including five compound heterozygotes and one heterozygote in whom a second variant was not identified (Iolascon et al. 2000; Servedio et al. 2005; Maruo et al. 2015). The variant was also found in one unaffected heterozygous parent of an affected individual. The p.Val225Gly variant was absent from 150 total controls but is reported at a frequency of 0.00212 in the South Asian population of the Exome Aggregation Consortium. Enzyme activity of the p.Val225Gly variant protein was found to be 61% as compared to wild type (Maruo et al. 2015). Based on the evidence, the p.Val225Gly variant is classified as likely pathogenic for Crigler-Najjar syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This sequence change replaces valine with glycine at codon 225 of the UGT1A1 protein (p.Val225Gly). The valine residue is weakly conserved and there is a moderate physicochemical difference between valine and glycine. This variant is present in population databases (rs35003977, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hyperbilirubinemia (PMID: 11182932, 15712364, 26697581). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 160239). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt UGT1A1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects UGT1A1 function (PMID: 26697581). For these reasons, this variant has been classified as Pathogenic.

The UGT1A1 c.674T>G; p.Val225Gly variant (rs35003977), is reported in the literature in individuals with Crigler-Najjar syndrome or Gilbert syndrome with other UGT1A1 variants in cis and/or trans (Iolascon 2000, Maruo 2015, Perretti 2007, Rodrigues 2012). Functional studies show that the variant protein enzymatic activity is reduced compared to that of the wildtype UGT1A1 protein (Maruo 2015). The p.Val225Gly variant is also reported in ClinVar (Variation ID: 160239). It is observed in the general population with an overall allele frequency of 0.05% (153/282862 alleles, including 1 homozygote) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.291). Based on available information, the clinical significance of this variant is uncertain at this time. References: Iolascon A et al. Crigler-Najjar syndrome type II resulting from three different mutations in the bilirubin uridine 5'-diphosphate-glucuronosyltransferase (UGT1A1) gene. J Med Genet. 2000 Sep;37(9):712-3. PMID: 11182932. Maruo Y et al. Two Different UGT1A1 Mutations causing Crigler-Najjar Syndrome types I and II in an Iranian Family. J Gastrointestin Liver Dis. 2015 Dec;24(4):523-6. PMID: 26697581. Perretti A et al. Clinical utility of electrophysiological evaluation in Crigler-Najjar syndrome. Neuropediatrics. 2007 Aug;38(4):173-8. PMID: 18058623. Rodrigues C et al. Impact of UGT1A1 gene variants on total bilirubin levels in Gilbert syndrome patients and in healthy subjects. Blood Cells Mol Dis. 2012 Mar 15;48(3):166-72. PMID: 22325916.

The c.674T>G (p.V225G) alteration is located in exon 1 (coding exon 1) of the UGT1A1 gene. This alteration results from a T to G substitution at nucleotide position 674, causing the valine (V) at amino acid position 225 to be replaced by a glycine (G). Based on data from gnomAD, the G allele has an overall frequency of 0.054% (153/282862) total alleles studied. The highest observed frequency was 0.265% (81/30616) of South Asian alleles. This variant has been detected in the compound heterozygous state with other UGT1A1 variants in multiple individuals diagnosed with Crigler-Najjar syndrome (Iolascon, 2000; Servedio, 2005; Maruo, 2015). This amino acid position is not well conserved in available vertebrate species. Functional studies showed residual enzyme activity of the variant protein was 61% of wild type (Maruo, 2015). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

PM2, PM3, PS3

The UGT1A1 c.674T>G variant is predicted to result in the amino acid substitution p.Val225Gly. This variant has been reported in patients affected by Crigler-Najjar Syndrome or Gilbert Syndrome (Iolascon et al. 2000. PubMed ID: 11182932, reported as V224G; Rodrigues et al. 2012. PubMed ID: 22325916; Maruo et al. 2015. PubMed ID: 26697581). In vitro enzymatic activity analysis indicated that the relative glucuronidation activity of the variant protein towards bilirubin was reduced to ~60% of that of wild type (Maruo et al. 2015. PubMed ID: 26697581). Taken together, although we suspect that c.674T>G (p.Val225Gly) could be pathogenic, the clinical significance of this variant is classified as uncertain at this time.