2-43872094-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_022437.3(ABCG8):c.1083G>A(p.Trp361*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000946 in 1,614,050 control chromosomes in the GnomAD database, including 3 homozygotes. 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 0.00081 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00096 ( 3 hom. )

Consequence

ABCG8
NM_022437.3 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 8.86

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 16 ACMG points.

PVS1

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

PP5

Variant 2-43872094-G-A is Pathogenic according to our data. Variant chr2-43872094-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-43872094-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCG8	NM_022437.3 link	c.1083G>A	p.Trp361*	stop_gained	Exon 7 of 13	ENST00000272286.4	NP_071882.1	Q9H221-1
ABCG8	NM_001357321.2 link	c.1083G>A	p.Trp361*	stop_gained	Exon 7 of 13		NP_001344250.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCG8	ENST00000272286.4 link	c.1083G>A	p.Trp361*	stop_gained	Exon 7 of 13	1	NM_022437.3	ENSP00000272286.2		Q9H221-1
ABCG8	ENST00000644611.1 link	c.1095G>A	p.Trp365*	stop_gained	Exon 7 of 9			ENSP00000495423.1		A0A2R8Y6M1

Frequencies

GnomAD3 genomes

AF:

0.000815

AC:

124

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00116

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000927

AC:

233

AN:

251300

Hom.:

AF XY:

0.000869

AC XY:

118

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000752

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00254

Gnomad NFE exome

AF:

0.00122

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000960

AC:

1403

AN:

1461830

Hom.:

Cov.:

AF XY:

0.000942

AC XY:

685

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000671

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00274

Gnomad4 NFE exome

AF:

0.00105

Gnomad4 OTH exome

AF:

0.000894

GnomAD4 genome

AF:

0.000815

AC:

124

AN:

152220

Hom.:

Cov.:

AF XY:

0.000941

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00282

Gnomad4 NFE

AF:

0.00116

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000854

Hom.:

Bravo

AF:

0.000635

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.00111

AC:

135

EpiCase

AF:

0.00104

EpiControl

AF:

0.00142

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:8

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 13, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 09, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3_strong, PS4_moderate, PVS1 -

Dec 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Trp361*) 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 (rs137852987, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with sitosterolemia (PMID: 11099417, 12124998, 16029460, 24657386, 28521186). ClinVar contains an entry for this variant (Variation ID: 4967). For these reasons, this variant has been classified as Pathogenic. -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 24, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 16029460, 12124998, 31980526, 11099417, 24657386, 28521186, 31589614, 33269076, 31345219, 35096999, 11452359, 32088153) -

Jan 28, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sitosterolemia 1

Pathogenic:4

Mar 04, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ABCG8 c.1083G>A (p.Trp361X) 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. Truncations downstream of this position have been associated with Sitosterolemia in HGMD. The variant allele was found at a frequency of 0.00093 in 251300 control chromosomes (gnomAD). c.1083G>A has been reported in the literature in multiple individuals affected with Sitosterolemia (example: Lu_2001). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and laboratories classified the variant as pathogenic (n=5) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jul 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 22, 2023

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ABCG8 c.1083G>A variant is classified as Likely Pathogenic (PVS1, PM3) The ABCG8 c.1083G>A variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 361 (PVS1). This variant has been detected in trans with a pathogenic variant or as homozygous in many affected patients (PMID:16029460, 11099417, 11452359) (PM3). The variant has been reported in dbSNP (rs137852987) and as disease causing in the HGMD database (CM003582). It has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 4967). This variant has been reported in population databases (gnomAD 124/152220 alleles, 0 homs, total allele frequency 0.081%, highest allele frequency 0.28% in European non-Finnish). -

Nov 28, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ABCG8-related disorder

Pathogenic:1

Aug 01, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ABCG8 c.1083G>A variant is predicted to result in premature protein termination (p.Trp361*). This variant is well documented in the literature as one of the most common causative variants of autosomal recessive sitosterolemia (Berge et al. 2000. PubMed ID: 11099417; Heimerl et al. 2002. PubMed ID: 12124998; Lu et al. 2001. PubMed ID: 11452359; Rees et al. 2005. PubMed ID: 16029460). This variant is reported in 0.25% of alleles in individuals of European (Finnish) descent in gnomAD. Nonsense variants in ABCG8 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Sitosterolemia

Pathogenic:1

Nov 12, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ABCG8 c.1083G>A (p.Trp361Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. Across a selection of the available literature, the p.Trp361Ter variant was reported in a total 20 individuals with sitosterolemia, including seven homozygotes, 11 compound heterozygotes, and two heterozygotes in whom a second variant was not identified, and in two unaffected heterozygous family members of affected individuals (Berge et al. 2000; Lu et al. 2001; Heimerl et al. 2002; Rees et al. 2005; Hansel et al. 2014). The p.Trp361Ter variant was absent from 296 control subjects and is reported at a frequency of 0.002598 in the European (Finnish) population of the Genome Aggregation Database. Due to the potential impact of stop-gained variants, the p.Trp361Ter variant is classified as pathogenic for sitosterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Gallbladder disease 4;C2749759:Sitosterolemia 1

Pathogenic:1

Nov 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Pathogenic:1

May 29, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W361* pathogenic mutation (also known as c.1083G>A), located in coding exon 7 of the ABCG8 gene, results from a G to A substitution at nucleotide position 1083. This changes the amino acid from a tryptophan to a stop codon within coding exon 7. This mutation has been reported in the homozygous or compound heterozygous state (with a variety of other ABCG8 alterations) in multiple individuals with sitosterolemia (Berge KE et al. Science, 2000 Dec;290:1771-5; Lu K et al. Am. J. Hum. Genet., 2001 Aug;69:278-90; Heimer S et al. Hum. Mutat., 2002 Aug;20:151; Rees DC et al. Br. J. Haematol., 2005 Jul;130:297-309; Hansel B et al. Atherosclerosis, 2014 May;234:162-8; Buonuomo PS et al. Atherosclerosis, 2017 07;262:71-77). 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

0.33

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

Vest4

0.87

GERP RS

4.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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