Gene Validity Curation

HPS4 - Hermansky-Pudlak syndrome 4

Gene: HPS4 (HGNC:15844)
Classification - 05/27/2020
Disease: Hermansky-Pudlak syndrome 4 (MONDO_0013556)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: HPS4 was first reported in relation to Autosomal Recessive Hermasky-Pudlak syndrome 4 in 2002 (Suzuki et al., PMID: 11836498). At least 20 unique variants, mostly nonsense and frameshift, but also a few missense variants have been reported in humans. HPS4 is involved in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. Hermansky-Pudlak syndrome 4 is characterized by 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 9 probands in 7 publications (PMIDs: 24433314, 15108212, 30990103, 30791930, 29108692, 11836498, 31415434). 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: 11836498). Summary of Experimental Data: 5 Points This gene-disease association is supported by animal models and in vitro functional assays. The "light ear" or le mouse that carries a spontaneously occurring mutation in Hps4 recapitulates the human HPS phenotype (PMID: 11836498). Another spontaneously occurring HPS4 mutation is identified to be the cause of albinism in channel catfish (PMID: 28289846). HPS4 interacts with HPS1 to form BLOC-3, which is involved in the biogenesis of lysosome-related organelles (PMID: 11836498, 23103514). In summary, HPS4 is definitively associated with Autosomal Recessive Hermasky-Pudlak syndrome 4. 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 May 27, 2020 (SOP Version 7).
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 8
15
12
Suzuki T et al. 2002 Mar (PMID:11836498); Power B et al. 2019 Feb 21 (PMID:30791930); Wu W et al. 2019 Aug (PMID:31415434); Araki Y et al. 2014 Feb (PMID:24433314); Bachli EB et al. 2004 Jun 1 (PMID:15108212); Sandrock-Lang K et al. 2018 Mar (PMID:29108692);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 1
0.25
Bastida JM et al. 2019 Mar (PMID:30990103);
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
Suzuki T et al. 2002 Mar (PMID:11836498);
Protein Interaction 0.5 0 - 2 1 0.5
Carmona-Rivera C et al. 2013 Mar (PMID:23103514);
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 2 2.5 2.5
Suzuki T et al. 2002 Mar (PMID:11836498); Li Y et al. 2017 Jun (PMID:28289846);
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) 3.5

 


 

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 3.5 15.5 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
05/29/2020
EXPERT CURATION (DATE)
Definitive
05/27/2020
EVIDENCE SUMMARY
HPS4 was first reported in relation to Autosomal Recessive Hermasky-Pudlak syndrome 4 in 2002 (Suzuki et al., PMID: 11836498). At least 20 unique variants, mostly nonsense and frameshift, but also a few missense variants have been reported in humans. HPS4 is involved in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. Hermansky-Pudlak syndrome 4 is characterized by 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 9 probands in 7 publications (PMIDs: 24433314, 15108212, 30990103, 30791930, 29108692, 11836498, 31415434). 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: 11836498). Summary of Experimental Data: 5 Points This gene-disease association is supported by animal models and in vitro functional assays. The "light ear" or le mouse that carries a spontaneously occurring mutation in Hps4 recapitulates the human HPS phenotype (PMID: 11836498). Another spontaneously occurring HPS4 mutation is identified to be the cause of albinism in channel catfish (PMID: 28289846). HPS4 interacts with HPS1 to form BLOC-3, which is involved in the biogenesis of lysosome-related organelles (PMID: 11836498, 23103514). In summary, HPS4 is definitively associated with Autosomal Recessive Hermasky-Pudlak syndrome 4. 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 May 27, 2020 (SOP Version 7).