Gene Validity Curation

HPS1 - Hermansky-Pudlak syndrome 1

Gene: HPS1 (HGNC:5163)
Classification - 07/22/2019
Disease: Hermansky-Pudlak syndrome 1 (MONDO_0008748)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: HPS1 was first reported in relation to Autosomal Recessive Hermasky-Pudlak syndrome 1 in 1996 (Oh et al., PMID: 8896559). At least 36 unique variants including missense, in-frame indel, nonsense, frameshift, and large deletions have been reported in humans. HPS1 is involved in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. Hermansky-Pudlak syndrome 1 is characterized by severe oculocutaneous albinism and a bleeding diathesis, but in some cases, also pulmonary fibrosis and granulomatous colitis. 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 10 probands in 4 publications (PMIDs: 8896559, 9497254, 9705234, 27593200). 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: 9256466) Summary of Experimental Data: 5.5 Points This gene-disease association is supported by mouse models and in vitro functional assays. The "pale ear" or ep mouse that carries a spontaneously occurring mutation in Hps1 recapitulates the human HPS phenotype (PMID: 9256466, 9158155). HPS1 interacts with HPS4 to form BLOC-3, which is involved in the biogenesis of lysosome-related organelles (PMID: 12847290, 29190429, 25468649). In summary, HPS1 is definitively associated with Autosomal Recessive Hermasky-Pudlak syndrome 1. 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 June 26, 2019 (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 12
20
12
Shotelersuk V et al. 1998 Jun (PMID:9705234); Wei A et al. 2016 Nov (PMID:27593200); Oh J et al. 1996 Nov (PMID:8896559); Oh J et al. 1998 Mar (PMID:9497254); Ghafouri-Fard S et al. 2016 July 3 (PMID:27942505); Ito S et al. 2005 Oct (PMID:16185271);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 3
1.5
Wei A et al. 2016 Nov (PMID:27593200); Oh J et al. 1998 Mar (PMID:9497254);
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
1
Nazarian R et al. 2003 Jul 22 (PMID:12847290);
Protein Interaction 0.5 0 - 2 2 0.5
Nazarian R et al. 2003 Jul 22 (PMID:12847290); Martina JA et al. 2003 Aug 1 (PMID:12756248);
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
Kook S et al. 2018 May (PMID:29190429);
Models Non-human model organism 2 0 - 4 4 1 2.5 4
Gardner JM et al. 1997 Aug 19 (PMID:9256466);
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 1.5
Ikawa Y et al. 2015 Jan (PMID:25468649);
Total Experimental Evidence Points (Maximum 6) 5.5

 


 

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 5.5 17.5 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
07/22/2019
EXPERT CURATION (DATE)
Definitive
07/22/2019
EVIDENCE SUMMARY
HPS1 was first reported in relation to Autosomal Recessive Hermasky-Pudlak syndrome 1 in 1996 (Oh et al., PMID: 8896559). At least 36 unique variants including missense, in-frame indel, nonsense, frameshift, and large deletions have been reported in humans. HPS1 is involved in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. Hermansky-Pudlak syndrome 1 is characterized by severe oculocutaneous albinism and a bleeding diathesis, but in some cases, also pulmonary fibrosis and granulomatous colitis. 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 10 probands in 4 publications (PMIDs: 8896559, 9497254, 9705234, 27593200). 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: 9256466) Summary of Experimental Data: 5.5 Points This gene-disease association is supported by mouse models and in vitro functional assays. The "pale ear" or ep mouse that carries a spontaneously occurring mutation in Hps1 recapitulates the human HPS phenotype (PMID: 9256466, 9158155). HPS1 interacts with HPS4 to form BLOC-3, which is involved in the biogenesis of lysosome-related organelles (PMID: 12847290, 29190429, 25468649). In summary, HPS1 is definitively associated with Autosomal Recessive Hermasky-Pudlak syndrome 1. 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 June 26, 2019 (SOP Version 6).