rs137852987

chr2-43872094-G-Achr2-43872094-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_022437.3(ABCG8):c.1083G>A(p.Trp361Ter) 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 8.86

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]

ACMG classification

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/exons	MANE	UniProt
ABCG8	NM_022437.3	c.1083G>A	p.Trp361Ter	stop_gained	7/13	ENST00000272286.4
ABCG8	NM_001357321.2	c.1083G>A	p.Trp361Ter	stop_gained	7/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCG8	ENST00000272286.4	c.1083G>A	p.Trp361Ter	stop_gained	7/13	1	NM_022437.3	P1
ABCG8	ENST00000644611.1	c.1095G>A	p.Trp365Ter	stop_gained	7/9

Frequencies

GnomAD3 genomes AF: 0.000815 AC: 124 AN: 152220 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000869 AC XY: 118 AN XY: 135810

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.: 3 Cov.: 32 AF XY: 0.000942 AC XY: 685 AN XY: 727204

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.: 0 Cov.: 32 AF XY: 0.000941 AC XY: 70 AN XY: 74368

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.: 0

Bravo AF: 0.000635

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00111 AC: 135

EpiCase AF: 0.00104

EpiControl AF: 0.00142

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 13, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 28, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Sitosterolemia 1 Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 28, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 04, 2022	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Mar 22, 2023	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). -

ABCG8-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2024

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. -

Gallbladder disease 4;C2749759:Sitosterolemia 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 01, 2021

- -

Sitosterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Nov 12, 2018

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. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 29, 2022

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	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	46
Dann	Uncertain	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A
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

Other links and lift over

dbSNP: rs137852987; hg19: chr2-44099233;