Submissions for variant NM_000463.3(UGT1A1):c.1198A>G (p.Asn400Asp)

gnomAD frequency: 0.00001  dbSNP: rs28934877

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV004528106	SCV000915898	uncertain significance	UGT1A1-related disorder	2018-11-21	criteria provided, single submitter	clinical testing	The UGT1A1 c.1198A>G (p.Asn400Asp) missense variant has been reported in one study and is found in a total of three patients including one in a homozygous state with Crigler-Najjar syndrome type II (CN-II) and two in a heterozygous state with Gilbert syndrome (Labrune et al. 2002). The patient with CN-II carried a second homozygous variant in the TATA box promoter region identified as UGT1A1*37. The p.Asn400Asp variant was absent from 50 control chromosomes and is reported at a frequency of 0.00007 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the limited evidence, the p.Asn400Asp variant is classified as a variant of unknown significance but suspicious for pathogenicity for UGT1A1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005237372	SCV005888474	uncertain significance	not specified	2025-01-02	criteria provided, single submitter	clinical testing	Variant summary: UGT1A1 c.1198A>G (p.Asn400Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 249052 control chromosomes. c.1198A>G has been reported in the literature in a homozugous individual affected with UGT1A1-Related Disorders who was also homozygous for the UGT1A1*37 aka c.-40_-43dupTATA promoter expansion variant, which is likely pathogenic but not sufficient to explain the more severe presentation in this individual (example, Labrune_2002). 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. The following publication have been ascertained in the context of this evaluation (PMID: 12402338). The following publication has been ascertained in the context of this evaluation (PMID: 12402338). ClinVar contains an entry for this variant (Variation ID: 12286). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
OMIM	RCV000013079	SCV000033325	pathogenic	Crigler-Najjar syndrome, type II	2002-11-01	no assertion criteria provided	literature only
OMIM	RCV000013080	SCV000033326	affects	Gilbert syndrome	2002-11-01	no assertion criteria provided	literature only