ClinVar Miner

Submissions for variant NM_000463.3(UGT1A1):c.524T>A (p.Leu175Gln)

gnomAD frequency: 0.00005  dbSNP: rs72551341
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000726992 SCV000704789 other not provided 2018-03-08 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000726992 SCV002047714 likely pathogenic not provided 2020-12-22 criteria provided, single submitter clinical testing The UGT1A1 c.524T>A; p.Leu175Gln variant (rs72551341) is reported in the literature in the homozygous or compound heterozygous state in individuals affected with Crigler-Najjar syndrome type II (Kadakol 2001, Seppen 1994). Functional analyses of the variant protein show significantly reduced bilirubin glucuronidation activity (Seppen 1994, Sneitz 2010). This variant is also reported in ClinVar (Variation ID: 12285). This variant is found in the non-Finnish European population with an allele frequency of 0.009% (11/113682 alleles) in the Genome Aggregation Database. The leucine at codon 175 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.494). Based on available information, this variant is considered to be likely pathogenic. References: Kadakol A et al. Interaction of coding region mutations and the Gilbert-type promoter abnormality of the UGT1A1 gene causes moderate degrees of unconjugated hyperbilirubinaemia and may lead to neonatal kernicterus. J Med Genet. 2001 Apr;38(4):244-9. Seppen J et al. Discrimination between Crigler-Najjar type I and II by expression of mutant bilirubin uridine diphosphate-glucuronosyltransferase. J Clin Invest. 1994 Dec;94(6):2385-91. Sneitz N et al. Crigler-Najjar syndrome in The Netherlands: identification of four novel UGT1A1 alleles, genotype-phenotype correlation, and functional analysis of 10 missense mutants. Hum Mutat. 2010 Jan;31(1):52-9.
Invitae RCV000726992 SCV002317673 likely pathogenic not provided 2023-10-13 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 175 of the UGT1A1 protein (p.Leu175Gln). This variant is present in population databases (rs72551341, gnomAD 0.009%). This missense change has been observed in individual(s) with UGT1A1-related conditions (PMID: 7989595, 11013440, 11370628, 23290513). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as *12. ClinVar contains an entry for this variant (Variation ID: 12285). 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. Experimental studies have shown that this missense change affects UGT1A1 function (PMID: 7989595, 9028453, 19830808). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
PreventionGenetics, part of Exact Sciences RCV003934828 SCV004751923 pathogenic UGT1A1-related condition 2024-01-31 criteria provided, single submitter clinical testing The UGT1A1 c.524T>A variant is predicted to result in the amino acid substitution p.Leu175Gln. This variant has been reported to be causative for Crigler-Najjar type 2 (Seppen et al. 1994. PubMed ID: 7989595). In vitro functional analysis indicated that the p.Leu175Gln change results in a significant loss of enzymatic activity (~4.6% of wild type) (Sneitz et al. 2010. PubMed ID: 19830808). At PreventionGenetics, we previously detected this variant, along with a protein-truncating variant, in an unrelated patient with suspected Crigler-Najjar syndrome. This variant is reported in 0.0097% of alleles in individuals of European (Non-Finnish) descent in gnomAD. We classify this variant as pathogenic.
OMIM RCV000013078 SCV000033324 pathogenic Crigler-Najjar syndrome, type II 2001-04-01 no assertion criteria provided literature only

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