Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

ACTC1 : Hypertrophic cardiomyopathy

MONDO:0005045 | ORPHA:217569 | OMIM:612098
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
6.00
6
Olson TM et al. 2000 Sep (PMID:10966831);
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
5.00
5
Mogensen J et al. 1999 May 15 (PMID:10330430); Olson TM et al. 2000 Sep (PMID:10966831); Arad M et al. 2005 Nov 1 (PMID:16267253); Monserrat L et al. 2007 Aug (PMID:17611253);
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 Evidence of segregation in one or more families   Sequencing Method 0-3 3
1.50
1.5  
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
3-4.99 1 2
Olson TM et al. 2000 Sep (PMID:10966831); Arad M et al. 2005 Nov 1 (PMID:16267253);
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Scores PMIDs/Notes
Points/Study Max Points Tally
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
2.00
Walsh R et al. 2017 Feb (PMID:27532257);
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Function Biochemical Function 0.5 0 - 2 2
2
Protein Interaction 0.5 0 - 2 1.00
Chow ML et al. 2014 May 15 (PMID:24736382); Haase H et al. 2006 May (PMID:16675844);
Expression 0.5 0 - 2 1.00
Fagerberg L et al. 2014 Feb (PMID:24309898);
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 0.50
Müller M et al. 2012 Oct (PMID:22643837);
Models Non-human model organism 2 0 - 4 4 3.00 3
Song W et al. 2011 Aug 5 (PMID:21622575); Song W et al. 2013 Jun 1 (PMID:23604709);
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 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
EXPERT CURATION (DATE)
DEFINITIVE
09/05/2017
This classification was approved by the Hypertrophic Cardiomyopathy Gene Curation Expert Panel.