chr12-21222355-C-T

Variant names:

• chr12-21222355-C-T
• rs71581941
• NM_006446.5:c.1738C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_Strong BS1_Supporting

The NM_006446.5(SLCO1B1):​c.1738C>T​(p.Arg580*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 18)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: SLCO1B1 NM_006446.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 0.885

Genes affected

SLCO1B1 (HGNC:10959): (solute carrier organic anion transporter family member 1B1) This gene encodes a liver-specific member of the organic anion transporter family. The encoded protein is a transmembrane receptor that mediates the sodium-independent uptake of numerous endogenous compounds including bilirubin, 17-beta-glucuronosyl estradiol and leukotriene C4. This protein is also involved in the removal of drug compounds such as statins, bromosulfophthalein and rifampin from the blood into the hepatocytes. Polymorphisms in the gene encoding this protein are associated with impaired transporter function. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PP5: Variant 12-21222355-C-T is Pathogenic according to our data. Variant chr12-21222355-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 30437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00132 (711/538442) while in subpopulation MID AF= 0.0208 (32/1542). AF 95% confidence interval is 0.0151. There are 2 homozygotes in gnomad4_exome. There are 377 alleles in male gnomad4_exome subpopulation. Median coverage is 12. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLCO1B1	NM_006446.5	c.1738C>T	p.Arg580*	stop_gained	Exon 13 of 15	ENST00000256958.3	NP_006437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLCO1B1	ENST00000256958.3	c.1738C>T	p.Arg580*	stop_gained	Exon 13 of 15	1	NM_006446.5	ENSP00000256958.2

Frequencies

GnomAD3 genomes AF: 0.00165 AC: 158 AN: 95992 Hom.: 1 Cov.: 18

Gnomad AFR AF: 0.000971

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00331

Gnomad ASJ AF: 0.00268

Gnomad EAS AF: 0.00400

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00183

Gnomad MID AF: 0.0833

Gnomad NFE AF: 0.00146

Gnomad OTH AF: 0.00409

GnomAD3 exomes AF: 0.00164 AC: 297 AN: 181496 Hom.: 2 AF XY: 0.00170 AC XY: 170 AN XY: 99870

Gnomad AFR exome AF: 0.000832

Gnomad AMR exome AF: 0.00315

Gnomad ASJ exome AF: 0.00205

Gnomad EAS exome AF: 0.00424

Gnomad SAS exome AF: 0.000584

Gnomad FIN exome AF: 0.000876

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.00523

GnomAD4 exome AF: 0.00132 AC: 711 AN: 538442 Hom.: 2 Cov.: 12 AF XY: 0.00139 AC XY: 377 AN XY: 272138

Gnomad4 AFR exome AF: 0.00163

Gnomad4 AMR exome AF: 0.00291

Gnomad4 ASJ exome AF: 0.00152

Gnomad4 EAS exome AF: 0.00362

Gnomad4 SAS exome AF: 0.000746

Gnomad4 FIN exome AF: 0.00127

Gnomad4 NFE exome AF: 0.00104

Gnomad4 OTH exome AF: 0.00260

GnomAD4 genome AF: 0.00162 AC: 156 AN: 96026 Hom.: 1 Cov.: 18 AF XY: 0.00186 AC XY: 81 AN XY: 43466

Gnomad4 AFR AF: 0.000970

Gnomad4 AMR AF: 0.00330

Gnomad4 ASJ AF: 0.00268

Gnomad4 EAS AF: 0.00400

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00183

Gnomad4 NFE AF: 0.00146

Gnomad4 OTH AF: 0.00408

Alfa AF: 0.00173 Hom.: 6

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00163 AC: 198

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rotor syndrome Pathogenic:9

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3+PP4+PVS1 -

Feb 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 29, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Department of Traditional Chinese Medicine, Fujian Provincial Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Dec 13, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 30, 2024

3billion, Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Nov 16, 2022

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

not provided Pathogenic:1

Nov 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SLCO1B1-related disorder Pathogenic:1

Aug 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.41
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.54	D
Vest4		0.91
GERP RS		3.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs71581941; hg19: chr12-21375289; COSMIC: COSV57012657;