Gene Validity Curation

APOB - hypercholesterolemia, autosomal dominant, type b

Gene: APOB (HGNC:603)
Classification - 11/14/2018
Disease: hypercholesterolemia, autosomal dominant, type b (MONDO_0007751)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: General Gene Curation EP Contributors:
  • UNC Biocuration Core
Evidence Summary: The APOB gene has been reported in association with hypercholesterolemia (autosomal dominant) and hypobetalipoproteinemia (autosomal recessive). The relationship between APOB and hypercholesterolemia (autosomal dominant) was evaluated using the ClinGen Clinical Validity Framework. Variants in APOB were first reported in humans with hypercholesterolemia as early as 1989 (Soria et al., PMID: 2563166). At least 7 variants (missense) in at least 13 probands in 6 publications been reported in humans (PMIDs: 24498611, 24234650, 15135245, 22408029, 2563166, 7627691). Variants in this gene segregated with disease in at least 41 family members. This gene-disease relationship has been studied in at least 1 case-control study at the single variant level with an odds ratio of 78 (95% CI 16-388, p=0.0001) (PMID: 9603795). The mechanism for disease involves mainly heterozygous missense variants resulting in defective apo B100 on LDL particles that fails to bind to LDLR (PMID: 29219151). The gene-disease association is also supported by in vitro studies and animal models. In summary, APOB is definitively associated with autosomal dominant hypercholesterolemia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen General Gene Curation EP on 11/14/2018.
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 13
6.25
6.25
Thomas ER et al. 2013 Sep (PMID:24498611); Alves AC et al. 2014 Apr 1 (PMID:24234650); Soufi M et al. 2004 May (PMID:15135245); Motazacker MM et al. 2012 Jun (PMID:22408029); Soria LF et al. 1989 Jan (PMID:2563166); Gaffney D et al. 1995 Aug (PMID:7627691);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 6.62 4
Motazacker MM et al. 2012 Jun (PMID:22408029); Soria LF et al. 1989 Jan (PMID:2563166);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 6.62    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12 1
3
3
Tybjaerg-Hansen A et al. 1998 May 28 (PMID:9603795);
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 10.75
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
2
2
Boren J et al. 1998 Mar 1 (PMID:9486979);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
Innerarity TL et al. 1987 Oct (PMID:3477815);
Models Non-human model organism 2 0 - 4 4 1 2 2
Callow MJ et al. 1994 Mar 15 (PMID:8134359);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 4.5

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 10.75 4.5 15.25 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
06/24/2020
EXPERT CURATION (DATE)
Definitive
11/14/2018
EVIDENCE SUMMARY
The APOB gene has been reported in association with hypercholesterolemia (autosomal dominant) and hypobetalipoproteinemia (autosomal recessive). The relationship between APOB and hypercholesterolemia (autosomal dominant) was evaluated using the ClinGen Clinical Validity Framework. Variants in APOB were first reported in humans with hypercholesterolemia as early as 1989 (Soria et al., PMID: 2563166). At least 7 variants (missense) in at least 13 probands in 6 publications been reported in humans (PMIDs: 24498611, 24234650, 15135245, 22408029, 2563166, 7627691). Variants in this gene segregated with disease in at least 41 family members. This gene-disease relationship has been studied in at least 1 case-control study at the single variant level with an odds ratio of 78 (95% CI 16-388, p=0.0001) (PMID: 9603795). The mechanism for disease involves mainly heterozygous missense variants resulting in defective apo B100 on LDL particles that fails to bind to LDLR (PMID: 29219151). The gene-disease association is also supported by in vitro studies and animal models. In summary, APOB is definitively associated with autosomal dominant hypercholesterolemia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen General Gene Curation EP on 11/14/2018.