Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

FLNC : Myofibrillar myopathy

MONDO:0018943 | ORPHA:171445 | OMIM:609524
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
6.00
6
Vorgerd M et al. 2005 Aug (PMID:15929027); Kley RA et al. 2007 Dec (PMID:18055494); Shatunov A et al. 2009 May (PMID:19050726); Kley RA et al. 2012 Sep (PMID:22961544); Luan X et al. 2010 Jun (PMID:20417099); Avila-Smirnow D et al. 2016 Oct (PMID:27633507); (PMIDs 15929027 and 18055494 are about the same family and were scored together. Also PMIDs 19050726 and 22961544 had a report of the same proband/family and scored together.)
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
Vorgerd M et al. 2005 Aug (PMID:15929027); Kley RA et al. 2007 Dec (PMID:18055494); (LOD= 4.879 Haplotype and candidate)
3-4.99 1 2
Avila-Smirnow D et al. 2016 Oct (PMID:27633507); (eLOD= 2.4, candidate)
≥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
Total Genetic Evidence Points (Maximum 12) 7.5
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
2
Fürst DO et al. 2013 Jan (PMID:23109048);
Protein Interaction 0.5 0 - 2 1.00
Fürst DO et al. 2013 Jan (PMID:23109048);
Expression 0.5 0 - 2 0.50
Xie Z et al. 1998 Oct 29 (PMID:9791010); van der Ven PF et al. 2000 Feb (PMID:10658210); (PMID 10658210 not scored due to unspecificity of the antibody used.)
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 0.50
Dalkilic I et al. 2006 Sep (PMID:16914736);
Models Non-human model organism 2 0 - 4 4 5.50 4
Dalkilic I et al. 2006 Sep (PMID:16914736); Deo RC et al. 2014 Dec 3 (PMID:25633252); Chevessier F et al. 2015 Dec 20 (PMID:26472074);
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 7.5 6 13.5 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
10/02/2017
EXPERT CURATION (DATE)
DEFINITIVE
12/12/2017
Approved by the ClinGen Hypertrophic cardiomyopathy Gene Curation Expert Panel