| 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 |
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Genetic Evidence
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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);
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| 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);
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| Autosomal Recessive Disease | Two variants in trans and at least one de novo or a predicted/proven null variant | 2 | 0-3 | 12 |
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| 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);
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| ≥5 | 1.5 | 3 | ||||||||||
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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 |
|
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| Aggregate Variant Analysis | 0-6 |
2.00
|
Walsh R et al. 2017 Feb (PMID:27532257);
|
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| Total Genetic Evidence Points (Maximum 12) | 12 |
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|
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);
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| Expression | 0.5 | 0 - 2 | 1.00 |
Fagerberg L et al. 2014 Feb (PMID:24309898);
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| 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);
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| 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);
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| Cell culture model | 1 | 0 - 2 | ||||||||||
| Rescue | Rescue in human | 2 | 0 - 4 |
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| 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 |
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| 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)*
|
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| CALCULATED CLASSIFICATION (DATE) |
DEFINITIVE
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| EXPERT CURATION (DATE) |
DEFINITIVE
09/05/2017
This classification was approved by the Hypertrophic Cardiomyopathy Gene Curation Expert Panel.
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