chr12-21222355-C-T

Position:

chr12-21222355-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBS1_Supporting

The NM_006446.5(SLCO1B1):c.1738C>T(p.Arg580Ter) 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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 0.885

Variant links:

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]

SLCO1B1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
SLCO1B1	NM_006446.5 linkuse as main transcript	c.1738C>T	p.Arg580Ter	stop_gained	13/15	ENST00000256958.3	NP_006437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLCO1B1	ENST00000256958.3 linkuse as main transcript	c.1738C>T	p.Arg580Ter	stop_gained	13/15	1	NM_006446.5	ENSP00000256958	P1

Frequencies

GnomAD3 genomes

AF:

0.00165

AC:

158

AN:

95992

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00170

AC XY:

170

AN XY:

99870

show subpopulations

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.:

Cov.:

AF XY:

0.00139

AC XY:

377

AN XY:

272138

show subpopulations

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.:

Cov.:

AF XY:

0.00186

AC XY:

AN XY:

43466

show subpopulations

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.:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00163

AC:

198

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rotor syndrome

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 13, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	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 -
Pathogenic, no assertion criteria provided	research	Department of Traditional Chinese Medicine, Fujian Provincial Hospital	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 29, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jul 30, 2024	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. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2021

- -

SLCO1B1-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 23, 2024

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

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.41

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.54

MutationTaster

Benign

1.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over