Gene Validity Curation

AP3B1 - Hermansky-Pudlak syndrome 2

Gene: AP3B1 (HGNC:566)
Classification - 02/26/2020
Disease: Hermansky-Pudlak syndrome 2 (MONDO_0011997)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: AP3B1 was first reported in relation to autosomal recessive Hermansky-Pudlak syndrome 2 in 1999 (Dell'Angelica et al., PMID 10024875). Hermansky-Pudlak syndrome 2 is a subtype of HPS, characterized by neutropenia and immune defects, in addition to oculocutaneous albinism and bleeding tendency. In some individuals, pulmonary fibrosis and granulomatous colitis are also observed. AP3B1 encodes the β1 subunit of adaptor complex-3, AP3, which is a coat protein complex that forms intracellular vesicles (Huizing et al., Hermansky-Pudlak Syndrome, GeneReviews). This complex is expressed ubiquitously. In the neurological tissues, however, the β2 subunit encoded by AP3B2 replaces β1 in the AP3 complex. At least 28 nonsense, frameshift and missense variants have been reported in humans (PMID: 28585318). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 12 POINTS Variants in this gene have been reported in at least 9 probands in 8 publications (PMIDs 28585318, 16537806, 19679886, 23215637, 10024875, 14566336, 16551969, 11809908) Variants in this gene segregated with disease in 3 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is homozygous loss of function (Huizing et al., Hermansky-Pudlak Syndrome, GeneReviews). Summary of Experimental Data: 4 POINTS This gene-disease association is supported by animal models and in vitro functional assays. The ‘Pearl’ mouse model is a spontaneously mutated mouse that expresses the HPS2 phenotype (PMID: 9931340). Yang et al., generated homozygous AP3B1 knock-out mice that showed similar phenotypes as that seen in HPS2 patients (PMID: 11058094). In-vitro studies in patient-derived cells and transfected cultures show defective intracellular protein trafficking in AP3B1 mutants (PMIDs 30630984, 11452004, 14566336, 10024875). In summary, AP3B1 is definitively associated with autosomal recessive Hermansky-Pudlak syndrome 2. 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 Hemostasis/Thrombosis gene curation expert panel on 2/26/20 (SOP Version 6).
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
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 6
10.5
12
de Boer M et al. 2017 Oct (PMID:28585318); Clark RH et al. 2003 Nov (PMID:14566336); Huizing M et al. 2002 Feb (PMID:11809908); Enders A et al. 2006 Jul 1 (PMID:16551969); Wenham M et al. 2010 Feb (PMID:19679886);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 3
2
Dell'Angelica EC et al. 1999 Jan (PMID:10024875); Jung J et al. 2006 Jul 1 (PMID:16537806); Kurnik K et al. 2012 Dec 5 (PMID:23215637);
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
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
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
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
0.5
0.5
Clark RH et al. 2003 Nov (PMID:14566336);
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
Karampini E et al. 2019 Jan 10. (PMID:30630984);
Models Non-human model organism 2 0 - 4 4 2 4 4
Feng L et al. 1999 Feb (PMID:9931340); Yang W et al. 2000 Nov (PMID:11058094);
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 1 0.5
Huizing M et al. 2001 Jul (PMID:11452004);
Total Experimental Evidence Points (Maximum 6) 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 12 5 17 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
03/26/2020
EXPERT CURATION (DATE)
Definitive
02/26/2020
EVIDENCE SUMMARY
AP3B1 was first reported in relation to autosomal recessive Hermansky-Pudlak syndrome 2 in 1999 (Dell'Angelica et al., PMID 10024875). Hermansky-Pudlak syndrome 2 is a subtype of HPS, characterized by neutropenia and immune defects, in addition to oculocutaneous albinism and bleeding tendency. In some individuals, pulmonary fibrosis and granulomatous colitis are also observed. AP3B1 encodes the β1 subunit of adaptor complex-3, AP3, which is a coat protein complex that forms intracellular vesicles (Huizing et al., Hermansky-Pudlak Syndrome, GeneReviews). This complex is expressed ubiquitously. In the neurological tissues, however, the β2 subunit encoded by AP3B2 replaces β1 in the AP3 complex. At least 28 nonsense, frameshift and missense variants have been reported in humans (PMID: 28585318). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 12 POINTS Variants in this gene have been reported in at least 9 probands in 8 publications (PMIDs 28585318, 16537806, 19679886, 23215637, 10024875, 14566336, 16551969, 11809908) Variants in this gene segregated with disease in 3 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is homozygous loss of function (Huizing et al., Hermansky-Pudlak Syndrome, GeneReviews). Summary of Experimental Data: 4 POINTS This gene-disease association is supported by animal models and in vitro functional assays. The ‘Pearl’ mouse model is a spontaneously mutated mouse that expresses the HPS2 phenotype (PMID: 9931340). Yang et al., generated homozygous AP3B1 knock-out mice that showed similar phenotypes as that seen in HPS2 patients (PMID: 11058094). In-vitro studies in patient-derived cells and transfected cultures show defective intracellular protein trafficking in AP3B1 mutants (PMIDs 30630984, 11452004, 14566336, 10024875). In summary, AP3B1 is definitively associated with autosomal recessive Hermansky-Pudlak syndrome 2. 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 Hemostasis/Thrombosis gene curation expert panel on 2/26/20 (SOP Version 6).