Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

GLA : Fabry disease

HGNC:4296 | MONDO_0010526
Mode of Inheritance: X-linked inheritance (HP:0001417)
Expert Panel: General Gene Curation
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 7 8.5 8.5
Shimotori M et al. 2008 Feb (PMID:18205205); Topaloglu AK et al. 1999 Dec (PMID:10666480);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 18
9
7
Bernstein HS et al. 1989 Apr (PMID:2539398); Shimotori M et al. 2008 Feb (PMID:18205205); Topaloglu AK et al. 1999 Dec (PMID:10666480);
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   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
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
1
1
Brady RO et al. 1967 Mar 10 (PMID:6020428);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
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 2 4
Ohshima T et al. 1997 Mar 18 (PMID:9122231); Taguchi A et al. 2013 Dec 15 (PMID:24094090);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4 1
2
Beck M et al. 2015 Jun (PMID:26937390);
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2 1 1
Ohshima T et al. 1997 Mar 18 (PMID:9122231);
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 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 12 5 17 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
02/15/2019
EXPERT CURATION (DATE)
Definitive
01/23/2019
EVIDENCE SUMMARY
The relationship between GLA and Fabry disease, an X-linked lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of March 3rd, 2017. Deficiency of the gene product, alpha-galactosidase A, was first reported in males with Fabry disease in 1967 (Brady et al; PMID 6023233), and variants in GLA were first associated with this disease in 1989 (Bernstein et al, PMID 2539398). Over 400 unique variants, including missense, nonsense, splice site, frameshift, in-frame deletions, and complex rearrangements, have been reported in humans (reviewed in Gal et al, 2006, PMID 21290673; Mehta, 2017, PMID 20301469). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Twenty-five variants were curated in 25 probands from 3 publications (Bernstein et al, 1989, PMID 2539398; Topaloglu et al, 1989, PMID 10666480; Shimotori et al, 2008, PMID 18205205). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism for disease is loss of function. This gene-disease association is supported by the function of the gene product (Brady et al, 1967, PMID 6020428) animal models and rescue (Oshima et al, 1997, PMID 9122231; Taguchi et al, 2013, PMID 24094090), and studies of the clinical impact of enzyme replacement therapy in humans (Beck et al, 2015, PMID 26937390). In summary, GLA is definitively associated with Fabry disease. This association has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.