Submissions for variant NM_000463.3(UGT1A1):c.1324C>T (p.Arg442Cys)

gnomAD frequency: 0.00009  dbSNP: rs143033456

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725932	SCV000340622	uncertain significance	not provided	2016-04-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000725932	SCV000572957	uncertain significance	not provided	2017-02-13	criteria provided, single submitter	clinical testing	The R442C variant in the UGT1A1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R442C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R442C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret R442C as a variant of uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000765634	SCV000896962	uncertain significance	Bilirubin, serum level of, quantitative trait locus 1; Crigler-Najjar syndrome type 1; Lucey-Driscoll syndrome; Crigler-Najjar syndrome, type II; Gilbert syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001139988	SCV001300193	uncertain significance	Crigler-Najjar syndrome	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). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000725932	SCV001471397	uncertain significance	not provided	2022-12-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000725932	SCV004237503	uncertain significance	not provided	2022-04-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000725932	SCV004559740	uncertain significance	not provided	2024-09-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 442 of the UGT1A1 protein (p.Arg442Cys). This variant is present in population databases (rs143033456, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with UGT1A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 286999). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt UGT1A1 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV004737419	SCV005344472	uncertain significance	UGT1A1-related disorder	2024-07-25	no assertion criteria provided	clinical testing	The UGT1A1 c.1324C>T variant is predicted to result in the amino acid substitution p.Arg442Cys. To our knowledge, this variant has not been reported in the literature in individuals affected with UGT1A1-related conditions. This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.