rs137852991

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_022437.3(ABCG8):c.1234C>T(p.Arg412Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

ABCG8
NM_022437.3 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 2.18

Variant links:

Genes affected

ABCG8 (HGNC:13887): (ATP binding cassette subfamily G member 8) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the White subfamily. The protein encoded by this gene functions to exclude non-cholesterol sterol entry at the intestinal level, promote excretion of cholesterol and sterols into bile, and to facilitate transport of sterols back into the intestinal lumen. It is expressed in a tissue-specific manner in the liver, intestine, and gallbladder. This gene is tandemly arrayed on chromosome 2, in a head-to-head orientation with family member ABCG5. Mutations in this gene may contribute to sterol accumulation and atherosclerosis, and have been observed in patients with sitosterolemia. [provided by RefSeq, Jul 2008]

ABCG8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-43873809-C-T is Pathogenic according to our data. Variant chr2-43873809-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-43873809-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCG8	NM_022437.3 linkuse as main transcript	c.1234C>T	p.Arg412Ter	stop_gained	9/13	ENST00000272286.4
ABCG8	NM_001357321.2 linkuse as main transcript	c.1231C>T	p.Arg411Ter	stop_gained	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCG8	ENST00000272286.4 linkuse as main transcript	c.1234C>T	p.Arg412Ter	stop_gained	9/13	1	NM_022437.3	P1	Q9H221-1
ABCG8	ENST00000644611.1 linkuse as main transcript	c.1246C>T	p.Arg416Ter	stop_gained	9/9

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000994

AC:

AN:

251416

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000115

AC:

168

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000122

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000125

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.000170

ExAC

AF:

0.000107

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 13, 2023	This sequence change creates a premature translational stop signal (p.Arg412*) in the ABCG8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCG8 are known to be pathogenic (PMID: 11452359, 15375183, 16029460). This variant is present in population databases (rs137852991, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of ABCG8-related conditions (PMID: 11099417, 32088153). ClinVar contains an entry for this variant (Variation ID: 4972). For these reasons, this variant has been classified as Pathogenic. -

Sitosterolemia 1

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 07, 2022	- -

ABCG8-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 19, 2024

The ABCG8 c.1234C>T variant is predicted to result in premature protein termination (p.Arg412*). This variant has been reported in individuals with sitosterolaemia (Berge et al. 2000. PubMed ID: 11099417; Heimerl et al. 2002. PubMed ID: 12124998). This variant is reported in 0.023% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in ABCG8 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Sitosterolemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

The ABCG8 c.1234C>T (p.Arg412Ter) is a stop-gained variant that has been reported in four studies in which it is found in a total of five individuals with sitosterolemia, all in a compound heterozygous state (Berge et al. 2000; Lu et al. 2001; Lee et al. 2001; Heimerl et al. 2002). The p.Arg412Ter variant was absent from 592 control alleles but is reported at a frequency of 0.00026 in the Latino population of the Exome Aggregation Consortium. Due to the potential impact of stop-gained variants, the p.Arg412Ter variant is classified as pathogenic for sitosterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 22, 2023

The p.R412* pathogenic mutation (also known as c.1234C>T), located in coding exon 9 of the ABCG8 gene, results from a C to T substitution at nucleotide position 1234. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alteration has been reported as compound heterozygous with additional alterations in ABCG8 in individuals with sitosterolemia (Berge KE et al. Science, 2000 Dec;290:1771-5; Lee MH et al. Curr Opin Lipidol, 2001 Apr;12:141-9; Lu K et al. Am J Hum Genet, 2001 Aug;69:278-90; Heimerl S et al. Hum Mutat, 2002 Aug;20:151; Xia Y et al. J Clin Lipidol, 2022 Dec;16:40-51). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.59

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.96

MutationTaster

Benign

1.0

Vest4

0.98

GERP RS

4.2

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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