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
NM_022437.3 stop_gained
Scores
5
1
1
Clinical Significance
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]
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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
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ABCG8 | ENST00000272286.4 | c.1083G>A | p.Trp361* | stop_gained | Exon 7 of 13 | 1 | NM_022437.3 | ENSP00000272286.2 | ||
| ABCG8 | ENST00000644611.1 | c.1095G>A | p.Trp365* | stop_gained | Exon 7 of 9 | ENSP00000495423.1 |
Frequencies
GnomAD3 genomes 0.000815 AC: 124AN: 152220Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000927 AC: 233AN: 251300Hom.: 0 AF XY: 0.000869 AC XY: 118AN XY: 135810
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GnomAD4 exome AF: 0.000960 AC: 1403AN: 1461830Hom.: 3 Cov.: 32 AF XY: 0.000942 AC XY: 685AN XY: 727204
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GnomAD4 genome 0.000815 AC: 124AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.000941 AC XY: 70AN XY: 74368
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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
| 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) | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 09, 2024 | PM3_strong, PS4_moderate, PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Jan 28, 2022 | - - |
| 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 | 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 | Labcorp Genetics (formerly Invitae), Labcorp | Dec 29, 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. - |
Sitosterolemia 1 Pathogenic:4
| 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 28, 2023 | - - |
| 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). - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2005 | - - |
ABCG8-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
Vest4
0.87
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at