Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

GAA : glycogen storage disease II

HGNC:4065 | MONDO_0009290
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
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
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 4
10
12
Palmer RE et al. 2007 Jan (PMID:17056254); Huie ML et al. 1994 Jul (PMID:7981676); Hermans MM et al. 1993 Feb 1 (PMID:8094613); Rohrbach M et al. 2010 Dec (PMID:20882352);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 5
5.5
Pipo JR et al. 2003 Oct (PMID:14643388); Boerkoel CF et al. 1995 Apr (PMID:7717400); Oba-Shinjo SM et al. 2009 Nov (PMID:19588081); Huie ML et al. 1998 Mar 27 (PMID:9535769);
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
2
Brown BI et al. 1965 Oct 25 (PMID:4286143);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 3 1.5
Reuser AJ et al. 1987 Jun (PMID:3108320); Umapathysivam K et al. 2000 Sep (PMID:10973860); Bali DS et al. 2011 May (PMID:21484825);
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
Hermans MM et al. 1991 Jul 25 (PMID:1856189);
Models Non-human model organism 2 0 - 4 4 1 2 4
Raben N et al. 1998 Jul 24 (PMID:9668092);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4 1
3
Kishnani PS et al. 2006 Jul (PMID:16860134);
Rescue in non-human model organism 2 0 - 4 1
2
Fraites TJ et al. 2002 May (PMID:11991748);
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
02/15/2019
EXPERT CURATION (DATE)
Definitive
01/23/2019
EVIDENCE SUMMARY
The relationship between GAA and glycogen storage disease type II (GSD II; Pompe disease; acid maltase deficiency) was evaluated using the ClinGen Clinical Validity Framework as of June 26, 2017. Deficiency of the gene product, acid alpha-glucosidase (acid maltase) was first reported in individuals with GSD II by Hers in 1963, and variants in GAA were first associated with this disease 1991 (Hermans et al, MID 8401535; Zhong et al, 1652892; Martinuik et al, 1684505). Over 800 unique variants, including missense, nonsense, splice site, in frame insertions and deletions, frameshift, large deletions, and complex rearrangements have been reported in humans (http://cluster15.erasmusmc.nl/klgn/pompe/mutations.html?lang=en). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Fourteen variants were curated in 10 probands in 9 publications (Zhong et al, 1991, PMID 1652892; Hermans et al, 1993, PMID 8094613; Huie et al, 1994, PMID 7981676; Boerkoel et al, 1995, PMID 7717400; Huie et al, 1998, PMID 9535769; Pipo et al, 2003, PMID 14643388; Palmer et al, 2007, PMID 17056254; Oba-Shinjo et al, 2009, PMID 19588081; Rohrbach et al, 2010, PMID 20882352 ). 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 (Brown et al, 1965, PMID 4286143), abnormal synthesis, transport and processing, and deficient activity of acid alpha-glucosidase in cells from patients and non-patient cells expressing GAA variants (Hermans et al, 1991, PMID 1856189; Reuser et al, 1997, PMID 3108320; Umapathysivam et al, 2000, PMID 10973860; Bali et al, 2011, PMID 21484825), animal models (Raben et al, 1998, PMID 9668092), gene therapy in animal models (Fraites et al, 2002, PMID 11991748) and studies of the clinical impact of enzyme replacement therapy in humans (Kishnani et al, 2006, PMID 1680134). In summary, GAA is definitively associated with glycogen storage disease type II. This association has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.