Gene Validity Curation

AP3D1 - Hermansky-Pudlak syndrome 10; HPS10

Gene: AP3D1 (HGNC:568)
Classification - 02/26/2020
Disease: Hermansky-Pudlak syndrome 10; HPS10 (MONDO_0014885)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: NO Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: AP3D1 was first reported in relation to autosomal recessive Hermansky-Pudlak syndrome 10 in 2016 (Ammann et al., PMID: 26744459). Hermansky-Pudlak syndrome 10 is a subtype of HPS, characterized by neutropenia, immune defects and neurological manifestations, in addition to oculocutaneous albinism and bleeding tendency. AP3D1 encodes the δ subunit of the adaptor complex-3, AP3, which is a coat protein complex that forms intracellular vesicles (Huizing et al., Hermansky-Pudlak Syndrome, GeneReviews). The AP3D1 deficiency phenotype presents a phenotypic spectrum that has overlap with that observed with AP3B1 and AP3B2 deficiencies (PMID: 27889060). Only 2 reports have been published so far, each reporting one homozygous deletion variant. In addition, a 12kb deletion in the mouse Ap3d gene is reported to be causative of a phenotype in the “mocha” mice, which is similar to HPS10 in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Summary of Case Level Data: 4 POINTS Variants in this gene have been reported in at least 2 probands in 2 publications (PMID: 26744459 , 30472485). The mechanism for disease is expected to be homozygous loss of function (PMID: 26744459). Summary of Experimental Data: 4 POINTS This gene-disease association is supported by studies in a spontaneously occurring mouse mutation, the “mocha” mice and an experimental rescue in patient cells. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. Since the first report of this gene-disease relationship appeared only in 2016, the classification is likely to change in the future, as more evidence emerges.
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 2
4
4
Ammann S et al. 2016 Feb 25 (PMID:26744459); Mohammed M et al. 2018 Nov 22. (PMID:30472485);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
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) 4
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
Peden AA et al. 2002 Jan 21 (PMID:11807095);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 2 3.5
Kantheti P et al. 1998 Jul (PMID:9697856);
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 1 0.5
Peden AA et al. 2002 Jan 21 (PMID:11807095);
Rescue in patient cells 1 0 - 2 1 1
Ammann S et al. 2016 Feb 25 (PMID:26744459);
Total Experimental Evidence Points (Maximum 6) 4

 


 

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 4 4 8 NO
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)
Moderate
02/10/2020
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Limited
02/10/2020
REASON(S) FOR CHANGE
Although the experimental evidence is sufficient to classify this gene-disease relationship as moderate, the case-level evidence is obtained from only 2 probands. Per Gene Curation SOP Version 6, at least 3 unrelated probands harboring variants with sufficient supporting evidence for disease causality are required for a "Moderate" classification. Therefore, this gene-disease relationship is classified as "Limited" at this time.
EXPERT CURATION (DATE)
Limited
02/26/2020
EVIDENCE SUMMARY
AP3D1 was first reported in relation to autosomal recessive Hermansky-Pudlak syndrome 10 in 2016 (Ammann et al., PMID: 26744459). Hermansky-Pudlak syndrome 10 is a subtype of HPS, characterized by neutropenia, immune defects and neurological manifestations, in addition to oculocutaneous albinism and bleeding tendency. AP3D1 encodes the δ subunit of the adaptor complex-3, AP3, which is a coat protein complex that forms intracellular vesicles (Huizing et al., Hermansky-Pudlak Syndrome, GeneReviews). The AP3D1 deficiency phenotype presents a phenotypic spectrum that has overlap with that observed with AP3B1 and AP3B2 deficiencies (PMID: 27889060). Only 2 reports have been published so far, each reporting one homozygous deletion variant. In addition, a 12kb deletion in the mouse Ap3d gene is reported to be causative of a phenotype in the “mocha” mice, which is similar to HPS10 in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Summary of Case Level Data: 4 POINTS Variants in this gene have been reported in at least 2 probands in 2 publications (PMID: 26744459 , 30472485). The mechanism for disease is expected to be homozygous loss of function (PMID: 26744459). Summary of Experimental Data: 4 POINTS This gene-disease association is supported by studies in a spontaneously occurring mouse mutation, the “mocha” mice and an experimental rescue in patient cells. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. Since the first report of this gene-disease relationship appeared only in 2016, the classification is likely to change in the future, as more evidence emerges.