Submissions for variant NM_000463.3(UGT1A1):c.222C>A (p.Tyr74Ter)

dbSNP: rs72551340

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000501478	SCV000597837	pathogenic	Crigler-Najjar syndrome	2017-05-30	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000597815	SCV000703716	pathogenic	not provided	2016-11-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000597815	SCV001592122	pathogenic	not provided	2017-10-31	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in UGT1A1 are known to be pathogenic (PMID: 23290513). This variant has been reported in the literature in an individual affected with Crigler-Najjar syndrome (PMID: 11013440). ClinVar contains an entry for this variant (Variation ID: 437210). This variant is present in population databases (rs72551340, ExAC 0.001%). This sequence change creates a premature translational stop signal (p.Tyr74*) in the UGT1A1 gene. It is expected to result in an absent or disrupted protein product.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000597815	SCV003799445	pathogenic	not provided	2024-07-05	criteria provided, single submitter	clinical testing	The UGT1A1 c.222C>A; p.Tyr74Ter variant (rs72551340) is reported in the literature in one individual affected with Crigler-Najjar syndrome (Kadakol 2000). This variant is also reported as pathogenic by several sources in ClinVar (Variation ID: 437210). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, several downstream truncating variants have been described in affected individuals and are considered pathogenic (Kadakol 2000, Skierka 2013).Based on available information, this variant is classified as pathogenic. References: Kadakol A et al. Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: correlation of genotype to phenotype. Hum Mutat. 2000 Oct;16(4):297-306. PMID: 11013440. Skierka JM et al. UGT1A1 genetic analysis as a diagnostic aid for individuals with unconjugated hyperbilirubinemia. J Pediatr. 2013 Jun;162(6):1146-52, 1152.e1-2. PMID: 23290513.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000501478	SCV006072110	pathogenic	Crigler-Najjar syndrome	2025-03-19	criteria provided, single submitter	clinical testing	Variant summary: UGT1A1 c.222C>A (p.Tyr74X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 251444 control chromosomes. c.222C>A has been reported in the literature in at least one individual affected with Crigler-Najjar syndrome (e.g. Kadakol_2000). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 437210). Based on the evidence outlined above, the variant was classified as pathogenic.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000597815	SCV001958233	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000597815	SCV001973302	pathogenic	not provided		no assertion criteria provided	clinical testing