ClinVar Genomic variation as it relates to human health

The SLCO1B1 c.1738C>T (p.Arg580Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The variant has been described in two studies in which it is found in a homozygous state in a total of nine individuals (including three siblings) with Rotor syndrome, who are also homozygous for either a 7.2 kb deletion or 6.1 kb intronic insertion in the SLCO1B3 gene (van de Steeg et al. 2012; Kagawa et al. 2015). The p.Arg580Ter variant was found to be absent from 554 controls but is reported at a frequency of 0.01923 in the Japanese in Tokyo, Japan population of the 1000 Genomes Project. The p.Arg580Ter residue occurs in a highly conserved region of the protein. The predicted truncation results in the loss of half of two transmembrane domains as well as a cytoplasmic tail, which may affect transport activity (Kim et al. 2007). Based on the potential impact of stop-gained variants and the evidence from the literature, the p.Arg580Ter variant is classified as pathogenic for Rotor syndrome. Note: bi-allelic variants in both the SLCO1B1 and SLCO1B3 genes combined have been shown to cause Rotor syndrome. For an individual to be affected with Rotor syndrome, they must carry a pathogenic variant in both copies of the SLCO1B1 gene and in both copies of the SLCO1B3 gene. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

The SLCO1B1 c.1738C>T; p.Arg580Ter variant (rs71581941) is reported in the literature in individuals affected with Rotor Syndrome (Fang 2021, Kimura 2021, van de Steeg 2012, Zhou 2019). This variant is also reported in ClinVar (Variation ID: 30437). This variant is found in the general population with an overall allele frequency of 0.15% (307/199906 alleles, including 2 homozygotes) in the Genome Aggregation Database (v2.1.1). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES: Fang Y et al. Clinical and Genetic Spectra of Inherited Liver Disease in Children in China. Front Pediatr. 2021 PMID: 33763395 Kimura A et al. Rotor Syndrome: Glucuronidated Bile Acidemia From Defective Reuptake by Hepatocytes. Hepatol Commun. 2021 Apr. PMID: 33860121 van de Steeg E et al. Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. J Clin Invest. 2012 Feb. PMID: 22232210 Zhou D et al. Insertion of LINE-1 Retrotransposon Inducing Exon Inversion Causes a Rotor Syndrome Phenotype. Front Genet. 2019 PMID: 32082363

It is observed in the gnomAD v2.1.1, dataset at total allele frequency of 0.154%. Stop-gained (nonsense) - predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 25546334, 34354231). The variant has been reported to be associated with SLCO1B1-related disorder (ClinVar ID: VCV000030437 / 3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Variant summary: SLCO1B1 c.1738C>T (p.Arg580X) 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 0.0016 in 181496 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in SLCO1B1 causing Rotor Syndrome, allowing no conclusion about variant significance. c.1738C>T has been reported in the literature as homozygous genotype together with homozygous variants in the SLCO1B3 gene in multiple individuals affected with Rotor Syndrome (van de Steeg_ 2012, Zhou_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32082363, 22232210). ClinVar contains an entry for this variant (Variation ID: 30437). Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence variant is a single nucleotide substitution (C>T) at coding position 1738 in the SLCO1B1 gene which changes the Arg580 codon into an early termition sigl. As it occurs in exon 13 of 15, this variant is predicted to generate a non-functiol allele through the expression of a truncated protein or a loss of SLCO1B1 expression due to nonsense-mediated decay. This is a previously reported variant (ClinVar) which has been observed in homozygous or compound heterozygous state in many individuals with Rotor syndrome (PMID: 35797228, 22232210, 25546334, 35257483, 32082363, 33860121); all individuals additiolly had loss of function of the SLCO1B3 gene, suggesting that Rotor syndrome is caused by loss of function in both SLCO1B1 and SLCO1B3. This variant is present in 307/199906 alleles (0.1536%) in the gnomAD population database. Protein truncation would remove part of a transmembrane domain and cytoplasmic tail, which would compromise protein function (PMID: 18159134). Based on the available evidence, we consider this variant to be pathogenic. ACMG Criteria: PM3, PS4, PVS1

The SLCO1B1 c.1738C>T variant is predicted to result in premature protein termination (p.Arg580*). This variant is frequently documented in individuals affected with Rotor syndrome who are also homozygous for either a c.1747+1G>A splice-site variant in SLCO1B3 (Kagawa et al. 2015. PubMed ID: 25546334), a 7.2kb deletion encompassing exon 12 of SLCO1B3 (van de Steeg et al. 2012. PubMed ID: 22232210), a ~6.1 kb LINE-1 retrotransposon insertion in intron 3 of SLCO1B3 resulting in exon 4 inversion and exclusion from mature mRNA (Zhou et al. 2019. PubMed ID: 32082363; Kimura et al. 2021. PubMed ID: 33860121), or a ~6.3 kb LINE-1 retrotransposon insertion in intron 5 of SLCO1B3, resulting in skipping of exon 5 or exons 5-7 (Kagawa et al. 2015. PubMed ID: 25546334). This variant is reported in 0.39% of alleles in individuals of East Asian descent in gnomAD and is also documented in two homozygous individuals of unknown phenotype. Based on the available evidence, we classify this variant as likely pathogenic.