Gene Validity Curation

ANKRD1 - hypertrophic cardiomyopathy

Gene: ANKRD1 (HGNC:15819)
Classification - 05/01/2020
Disease: hypertrophic cardiomyopathy (MONDO_0005045)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: NO Contradictory Evidence: NO
Expert Panel: Hypertrophic Cardiomyopathy EP
Evidence Summary: The ANKRD1 gene has been associated with autosomal dominant hypertrophic cardiomyopathy in 3 probands in 2 publications. 3 unique missense variants have been reported in humans with no family history of cardiomyopathy. ANKRD1 was first associated with this disease in humans in 2009 (Arimura et al.). Experiments in Crocini et al. 2013 suggest a gain-of-function mechanism for variants in this gene. This gene-disease association is supported by expression studies in mature rat cardiomyocytes and the examination of contraction parameters using engineered heart tissues. In summary, there is limited evidence to support this gene-disease association. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association. This classification was approved by the ClinGen Hypertrophic Cardiomyopathy Working Group on 9/19/2017. This curation was reviewed for its association with hypertrophic cardiomyopathy (HCM) on April 17th, 2020. No new evidence, convincing or otherwise, has been published that would change this classification. In summary, there is still limited evidence to support this gene-disease association.
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 6
1.1
1.1
Arimura T et al. 2009 Jul 21 (PMID:19608031); Ng D et al. 2013 Aug (PMID:23861362); Cecconi M et al. 2016 Oct (PMID:27600940);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
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
0
Aggregate Variant Analysis 0-6 2
0
Walsh R et al. 2017 Feb (PMID:27532257); Walsh R et al. 2017 Dec 7 (PMID:28082330);
Total Genetic Evidence Points (Maximum 12) 1.1
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
Protein Interaction 0.5 0 - 2 1 0
Arimura T et al. 2009 Jul 21 (PMID:19608031);
Expression 0.5 0 - 2 1 1
Uhlén M et al. 2015 Jan 23 (PMID:25613900);
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
Cell culture model 1 0 - 2 2 1
Crocini C et al. 2013 May (PMID:23572067);
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) 2

 


 

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 1.1 2 3.1 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)
Limited
04/17/2020
EXPERT CURATION (DATE)
Limited
05/01/2020
EVIDENCE SUMMARY
The ANKRD1 gene has been associated with autosomal dominant hypertrophic cardiomyopathy in 3 probands in 2 publications. 3 unique missense variants have been reported in humans with no family history of cardiomyopathy. ANKRD1 was first associated with this disease in humans in 2009 (Arimura et al.). Experiments in Crocini et al. 2013 suggest a gain-of-function mechanism for variants in this gene. This gene-disease association is supported by expression studies in mature rat cardiomyocytes and the examination of contraction parameters using engineered heart tissues. In summary, there is limited evidence to support this gene-disease association. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association. This classification was approved by the ClinGen Hypertrophic Cardiomyopathy Working Group on 9/19/2017. This curation was reviewed for its association with hypertrophic cardiomyopathy (HCM) on April 17th, 2020. No new evidence, convincing or otherwise, has been published that would change this classification. In summary, there is still limited evidence to support this gene-disease association.