Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

MYL3 : Hypertrophic Cardiomyopathy

MONDO:0005045 | ORPHA:217569 | OMIM:608751
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
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
7.00
7
Poetter K et al. 1996 May (PMID:8673105); Arad M et al. 2005 Nov 1 (PMID:16267253); Fokstuen S et al. 2008 Jun (PMID:18409188); Nomura A et al. 2016 Feb (PMID:26443374); Alfares AA et al. 2015 Nov (PMID:25611685); Lee W et al. 2001 Feb (PMID:11174330); Richard P et al. 2003 May 6 (PMID:12707239); Fokstuen S et al. 2011 Aug (PMID:21239446); Almaas VM et al. 2013 Sep (PMID:23426552); Jaafar N et al. 2015 (PMID:26779504); Rubattu S et al. 2016 Jul 30 (PMID:27483260); Andersen PS et al. 2009 Mar (PMID:19035361); Chiou KR et al. 2015 Mar (PMID:25086479); Morita H et al. 2008 May 1 (PMID:18403758);
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
2.50
2.5  
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
Poetter K et al. 1996 May (PMID:8673105); Nomura A et al. 2016 Feb (PMID:26443374);
3-4.99 1 2
≥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) 11.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Function Biochemical Function 0.5 0 - 2 2
1.5
Protein Interaction 0.5 0 - 2 1.00
Petzhold D et al. 2011 Jun 1 (PMID:21262909); Haase H et al. 2006 May (PMID:16675844);
Expression 0.5 0 - 2 0.50
Fujimoto K et al. 1993 Jan (PMID:8417110);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1.00 1
Vemuri R et al. 1999 Feb 2 (PMID:9927691);
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) 2.5

 


 

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 11.5 2.5 14 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
12/22/2017
This classification was approved by the Hypertrophic Cardiomyopathy Gene Curation Expert Panel.