Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

DES : Myofibrillar myopathy

MONDO:0011076 | ORPHA:98909 | OMIM:601419
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
5.00
5
Sugawara M et al. 2000 Oct 10 (PMID:11061256); Dalakas MC et al. 2000 Mar 16 (PMID:10717012);
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
5.50
5.5
Goldfarb LG et al. 1998 Aug (PMID:9697706); Sjöberg G et al. 1999 Nov (PMID:10545598); Sugawara M et al. 2000 Oct 10 (PMID:11061256); Clemen CS et al. 2009 Mar (PMID:19105189); Dalakas MC et al. 2000 Mar 16 (PMID:10717012); Bär H et al. 2007 Apr (PMID:17221859);
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
≥5 1.5 3
Sjöberg G et al. 1999 Nov (PMID:10545598);
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
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
0.50
1
Tidball JG et al. 1992 Apr (PMID:1544366);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 0.50
Li ZL et al. 1989 May 30 (PMID:2673923);
Functional Alteration Patient cells 1 0 - 2 2
1
Non-patient cells 0.5 0 - 1 1.00
Bär H et al. 2005 Oct 18 (PMID:16217025);
Models Non-human model organism 2 0 - 4 4 4.00 4
Hnia K et al. 2015 Jun (PMID:25358400);
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) 6

 

 

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 6 18 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
08/25/2017
EXPERT CURATION (DATE)
DEFINITIVE
09/25/2017
Approved by Jonathan Berg, MD, PhD