Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

FGF3 : deafness with labyrinthine aplasia, microtia, and microdontia

HGNC:3681 | MONDO_0012541
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hearing Loss
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
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
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 7
10.5
12
Tekin M et al. 2007 Feb (PMID:17236138); Tekin M et al. 2008 Jun (PMID:18435799); Riazuddin S et al. 2011 Feb 9 (PMID:21306635); Sensi A et al. 2011 May (PMID:21480479);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 4
2
Tekin M et al. 2007 Feb (PMID:17236138); Tekin M et al. 2008 Jun (PMID:18435799); Alsmadi O et al. 2009 Jan (PMID:18701883); Riazuddin S et al. 2011 Feb 9 (PMID:21306635);
Segregation Evidence   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 26.76 6
Tekin M et al. 2007 Feb (PMID:17236138); Alsmadi O et al. 2009 Jan (PMID:18701883); Riazuddin S et al. 2011 Feb 9 (PMID:21306635);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 26.76    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
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 Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
0.5
2
Lahlou H et al. 2018 Jun 14 (PMID:29902227);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 2 2
Urness LD et al. 2018 Dec 18 (PMID:30504125); Olaya-Sánchez D et al. 2017 Jan (PMID:26995070);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 4 4
Mansour SL et al. 1993 Jan (PMID:8223243);
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
05/22/2019
EXPERT CURATION (DATE)
Definitive
05/21/2019
EVIDENCE SUMMARY
FGF3 was first reported in relation to autosomal recessive deafness with labyrinthine aplasia, microtia, and microdontiain (LAMM) syndrome in 2007 (Tekin et al., PMID 17236138). At least 11 variants (e.g. missense, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, experimental data. Variants in this gene have been reported in at least 12 probands in 6 publications (PMIDs 21480479, 21306635, 18435799, 17236138, 21306635, 18701883). Variants in this gene segregated with disease in at least 41 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence (12 pts.) has been reached. The mechanism for disease appears to be homozygous loss of function based on the variants observed in patients. This gene-disease association is supported by animal models, expression studies and in vitro functional assays (PMIDs 8223243, 26995070, 29902227, 30504125). In summary, FGF3 is definitively associated with autosomal recessive deafness with LAMM syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Expert Panel on 5/21/2019 (SOP Version 6).