Gene Validity Curation

ANO6 - Scott syndrome

Gene: ANO6 (HGNC:25240)
Classification - 05/27/2020
Disease: Scott syndrome (MONDO_0009885)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: ANO6 was first reported in relation to autosomal recessive Scott syndrome in 2010 (Suzuki J, et al., PMID: 21107324). At least 5 unique variants (nonsense, splicing, frameshift, and large deletion) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 3 probands in 3 publications (PMIDs: 21107324, 21511967, 27879994). Variants in this gene segregated with disease in 1 additional family member. The mechanism for disease is homozygous loss of function. This gene-disease relationship is supported by the biochemical function of ANO6 as a transmembrane protein essential for the calcium-dependent exposure of phosphatidylserine (PMID: 21107324), defects in which are responsible for a reduced catalytic platelet surface, which leads to reduced thrombin generation and impaired clot formation in patient cells (PMID: 27879994). Both dog and mouse models recapitulate the defect in phosphatidylserine exposure and bleeding abnormalities (PMIDs: 11895776, 23021219). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.
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 1
2
2
Suzuki J et al. 2010 Dec 9 (PMID:21107324);
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) 2
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
Suzuki J et al. 2010 Dec 9 (PMID:21107324);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1
1
1
Boisseau P et al. 2018 Mar (PMID:27879994);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 4 4
Brooks MB et al. 2002 Apr 1 (PMID:11895776); Yang H et al. 2012 Sep 28 (PMID:23021219);
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) 5.5

 


 

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 2 5.5 7.5 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)
Moderate
05/27/2020
EXPERT CURATION (DATE)
Moderate
05/27/2020
EVIDENCE SUMMARY
ANO6 was first reported in relation to autosomal recessive Scott syndrome in 2010 (Suzuki J, et al., PMID: 21107324). At least 5 unique variants (nonsense, splicing, frameshift, and large deletion) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 3 probands in 3 publications (PMIDs: 21107324, 21511967, 27879994). Variants in this gene segregated with disease in 1 additional family member. The mechanism for disease is homozygous loss of function. This gene-disease relationship is supported by the biochemical function of ANO6 as a transmembrane protein essential for the calcium-dependent exposure of phosphatidylserine (PMID: 21107324), defects in which are responsible for a reduced catalytic platelet surface, which leads to reduced thrombin generation and impaired clot formation in patient cells (PMID: 27879994). Both dog and mouse models recapitulate the defect in phosphatidylserine exposure and bleeding abnormalities (PMIDs: 11895776, 23021219). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.