Submissions for variant NM_000463.3(UGT1A1):c.923G>A (p.Gly308Glu)

gnomAD frequency: 0.00001  dbSNP: rs62625011

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV002247330	SCV002517454	likely pathogenic	Gilbert syndrome	2022-05-04	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003114188	SCV003799875	likely pathogenic	not provided	2022-08-18	criteria provided, single submitter	clinical testing	The UGT1A1 c.923G>A; p.Gly308Glu variant (rs62625011), also known as p.Gly309Glu and UGT1A1*11, is reported in the literature in the homozygous state in two individuals affected with Crigler-Najjar syndrome (Erps 1994, Gaidos 2006), and in the compound heterozygous state in five individuals affected with Gilbert syndrome and one affected with Crigler-Najjar syndrome (Costa 2006, Rodrigues 2012). In vitro functional analysis demonstrates reduced enzyme activity (Erps 1994). This variant is reported in ClinVar (Variation ID: 12272) but is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 308 is moderately conserved and computational analyses predict that this variant is deleterious (REVEL: 0.949). Based on available information, this variant is considered to be likely pathogenic. References: Costa E et al. Analysis of the UDP-glucuronosyltransferase gene in Portuguese patients with a clinical diagnosis of Gilbert and Crigler-Najjar syndromes. Blood Cells Mol Dis. 2006 Jan-Feb;36(1):91-7. PMID: 16269258. Erps LT et al. Identification of two single base substitutions in the UGT1 gene locus which abolish bilirubin uridine diphosphate glucuronosyltransferase activity in vitro. J Clin Invest. 1994 Feb;93(2):564-70. PMID: 7906695. Gajdos V et al. Successful pregnancy in a Crigler-Najjar type I patient treated by phototherapy and semimonthly albumin infusions. Gastroenterology. 2006 Sep;131(3):921-4. PMID: 16952560. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV003114188	SCV004226549	pathogenic	not provided	2023-03-29	criteria provided, single submitter	clinical testing	PP3, PP4, PM2, PM3, PS3, PS4_moderate
Labcorp Genetics (formerly Invitae), Labcorp	RCV003114188	SCV005727451	pathogenic	not provided	2024-06-28	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 308 of the UGT1A1 protein (p.Gly308Glu). This variant is present in population databases (rs62625011, gnomAD 0.009%). This missense change has been observed in individual(s) with hyperbilirubinemia (PMID: 7906695, 16269258, 22325916). 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 Gly309Glu. ClinVar contains an entry for this variant (Variation ID: 12272). 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 expected to disrupt UGT1A1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects UGT1A1 function (PMID: 7906695). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000013060	SCV000033306	pathogenic	Crigler-Najjar syndrome type 1	1994-02-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004737146	SCV005360771	pathogenic	UGT1A1-related disorder	2024-04-16	no assertion criteria provided	clinical testing	The UGT1A1 c.923G>A variant is predicted to result in the amino acid substitution p.Gly308Glu. This variant has been reported in the homozygous or compound heterozygous state in individuals with Gilbert syndrome, or Crigler-Najjar syndrome I or II (reported as Gly309Glu in Erps et al 1994. PubMed ID: 7906695; Costa et al 2006. PubMed ID: 16269258; Rodrigues et al 2012. PubMed ID: 22325916). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.