Gene Validity Curation

HPS3 - Hermansky-Pudlak syndrome 3

Gene: HPS3 (HGNC:15597)
Classification - 02/26/2020
Disease: Hermansky-Pudlak syndrome 3 (MONDO_0013555)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: The relationship between HPS3 and Hermasky-Pudlak syndrome 3, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of August 8, 2019. HPS3 was first reported in relation to Hermasky-Pudlak syndrome 3 in 2001 (Anikster, 2001, PMID: 11455388; Huizing, 2001, PMID: 11590544). At least 19 unique variants including nonsense, splice site, frameshift and large deletions have been reported in humans. Missense variants are not very common. HPS3 is involved in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. Hermansky-Pudlak syndrome 3 is characterized by a mild phenotype compared to HPS1, with minimal hypopigmentation, ocular rather than oculocutaneous albinism and a mild bleeding diathesis (PMID: 20301464). It is generally not associated with pulmonary fibrosis or granulomatous colitis. Evidence supporting this gene-disease relationship includes case-level data, family data and experimental data. Summary of Case Level Data: 12 Points Variants in this gene have been reported in at least 7 probands in 5 publications (PMID: 11455388, 11590544, 28284561, 27593200, 30791930). Variants in the gene segregated with 4 additional family members (PMID: 11455388). 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 (PMID: 20301464) Summary of Experimental Data: 5 Points This gene-disease association is supported by mouse models and in vitro functional assays. The "cocoa" or "coa" mouse that carries at least 4 diferent spontaneously occurring mutations in the mouse Hps3 gene recapitulates the human HPS phenotype (PMID: 11707070, 14718540). HPS3 interacts with HPS5 and HPS6 to form BLOC-2, which is involved in the biogenesis of lysosome-related organelles (PMID: 15675963, 15632015, 15030569, 14718540). In summary, HPS3 is definitively associated with autosomal recessive Hermasky-Pudlak syndrome 3. 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 GCEP on February 26, 2020 (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 7
13
12
Anikster Y et al. 2001 Aug (PMID:11455388); Huizing M et al. 2001 Nov (PMID:11590544); Wei A et al. 2016 Nov (PMID:27593200); Sandrock-Lang K et al. 2017 Sep (PMID:28284561); Power B et al. 2019 Feb 21 (PMID:30791930);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 0.5 0.5  
Candidate gene sequencing 2.41 1
Anikster Y et al. 2001 Aug (PMID:11455388);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 2.41    
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
1
1.5
Gautam R et al. 2004 Mar 26 (PMID:14718540);
Protein Interaction 0.5 0 - 2 1 0.5
Gautam R et al. 2004 Mar 26 (PMID:14718540);
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1
1
1
Richmond B et al. 2005 Feb (PMID:15675963);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 2.5 2.5
Suzuki T et al. 2001 Nov (PMID:11707070);
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) 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
02/26/2020
EXPERT CURATION (DATE)
Definitive
02/26/2020
EVIDENCE SUMMARY
The relationship between HPS3 and Hermasky-Pudlak syndrome 3, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of August 8, 2019. HPS3 was first reported in relation to Hermasky-Pudlak syndrome 3 in 2001 (Anikster, 2001, PMID: 11455388; Huizing, 2001, PMID: 11590544). At least 19 unique variants including nonsense, splice site, frameshift and large deletions have been reported in humans. Missense variants are not very common. HPS3 is involved in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. Hermansky-Pudlak syndrome 3 is characterized by a mild phenotype compared to HPS1, with minimal hypopigmentation, ocular rather than oculocutaneous albinism and a mild bleeding diathesis (PMID: 20301464). It is generally not associated with pulmonary fibrosis or granulomatous colitis. Evidence supporting this gene-disease relationship includes case-level data, family data and experimental data. Summary of Case Level Data: 12 Points Variants in this gene have been reported in at least 7 probands in 5 publications (PMID: 11455388, 11590544, 28284561, 27593200, 30791930). Variants in the gene segregated with 4 additional family members (PMID: 11455388). 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 (PMID: 20301464) Summary of Experimental Data: 5 Points This gene-disease association is supported by mouse models and in vitro functional assays. The "cocoa" or "coa" mouse that carries at least 4 diferent spontaneously occurring mutations in the mouse Hps3 gene recapitulates the human HPS phenotype (PMID: 11707070, 14718540). HPS3 interacts with HPS5 and HPS6 to form BLOC-2, which is involved in the biogenesis of lysosome-related organelles (PMID: 15675963, 15632015, 15030569, 14718540). In summary, HPS3 is definitively associated with autosomal recessive Hermasky-Pudlak syndrome 3. 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 GCEP on February 26, 2020 (SOP Version 6).