Gene Validity Curation

GBA - Gaucher disease

Gene: GBA (HGNC:4177)
Classification - 06/24/2020
Disease: Gaucher disease (MONDO_0018150)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: General Gene Curation EP
Evidence Summary: The relationship between GBA and Gaucher disease, an autosomal recessive condition that is the most common lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of June 20, 2020. GBA encodes the lysosomal enzyme glucocerebrosidase (glucosylceramidase) which breaks down the glycosphingolipid, glucocerebroside (glucosylceramide). The presence of Gaucher cells (macrophages filled with glucocerebroside) in the spleen, liver, and bone marrow of affected individuals is a distinguishing histological features of this disorder. Gaucher disease is multisystem disease characterized by hepatosplenomegaly, hematological abnormalities, bone disease, and neurological abnormalities. Historically, the disorder has been subclassified as type 1, the non-neuronopathic variant; type 2, the acute neuronopathic variant; type 3, the subacute neuronopathic variant and the collodion baby or neonatal variant (Sidransky 2004, PMID 15464415). Biallelic variants in GBA were first reported in patients with Gaucher disease in 1987 (Tsuji et al). Since then, over 200 variants have been reported. The mechanism of disease is loss of function. There is a clear genotype/phenotype correlation for some variants. For example, the mild p.Asn409Ser variant (formerly known as N370S) is found only in patients with type 1 disease, while p.Leu483Pro (formerly known as L444P) is associated with the neuronal subtypes. Molecular analysis of GBA is complicated by the presence of a highly homologous pseudogene, GBAP. In addition, the traditional variant nomenclature did not include the first 39 amino acids of the protein. These are now included based on the HGVS-recommended nomenclature. The four most common variants account for approximately 90% of the pathogenic variants in the Ashkenazi Jewish population and about 50-60% of pathogenic variants in non-Jewish populations (GeneReviews). These variants are c.84dupG (formerly known as 84GG), c.115+1G>A (formerly known as IVS2+1), p.Asn409Ser (formerly known as p.N370S), p.Leu483Pro (formerly known as p.L444P). Evidence supporting this gene-disease relationship includes case-level and experimental data. Ten unique variants (missense, nonsense, frameshift, splice site) from 13 probands in 9 publications were curated (Tsuji et al, 1987, PMID 2880291; Kolody et al, 1990, PMID 2117855; Beutler et al, 1991, PMID 1961718; He et al, 1992, PMID 1415223; Grace et al, 1997, PMID 9153297; Grace et al, 1999, PMID 10079102; Montfort et al, 2004, PMID 15146461; Haverkaemper et al, 2011, PMID 21455010; Beaujot et al, 2013, PMID 23749476). More information is available in the literature but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is also supported by the function of the gene product, glucocerebrosidase, which is consistent with the clinical features observed in patients with Gaucher disease (Pentchev et al, 1973, PMID 4768898; Boer et al, 2020, PMID 32182893), studies of induced pluripotent stem cells (iPSCs) derived from patients with Gaucher disease and differentiated into macrophages and neurons (Panicker et al, 2012, PMID 23071332), mouse models with variants corresponding to those found in human patients (Liu et al, 1999, PMID 9482915), the impact of culturing iPSCs from patients with Gaucher disease with recombinant glucocerebrosidase (Panicker et al, 2012, PMID 23071332), and the improvement in clinical symptoms in patients treated with enzyme replacement therapy (Barton et al, 1991; PMID 2023606). More information is available in the literature but the maximum score for experimental evidence (6 points) has been reached. In summary, GBA is definitively associated with Gaucher disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity classification was approved by the General GCEP on June 24, 2020. This clinical validity assessment includes data curated by Myriad Women’s Health. LUMPING AND SPLITTING: Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism AND inheritance pattern for Gaucher disease type I (MIM# 230800), type 2 (MIM# 230900), type 3 (MIM# 231000), type IIIc (231005), or perinatal lethal Gaucher disease (MIM# 608013). While these disease entities represent a wide range of clinical severity, the molecular mechanism is loss of function and the inheritance pattern is autosomal recessive for them all. Therefore, these disease entities have been lumped into one disease entity, Gaucher disease. We found differences in the inheritance pattern and phenotypic variability for risk of isolated late-onset Parkinson disease (MIM# 168600) and Lewy body dementia (MIM# 127750). While Parkinson disease and Lewy body dementia may occur at higher rates in individuals with Gaucher disease, Gaucher disease is associated with multi-system disease, as opposed to the increased risk of these isolated conditions occurring in individuals who are heterozygous for variants in GBA. Therefore, these disease entities are not included in this curation and may be curated for GBA at a later date.
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
9
12
He GS et al. 1992 Oct (PMID:1415223); Beutler E et al. 1991 Dec 1 (PMID:1961718); Beaujot J et al. 2013 Oct (PMID:23749476); Grace ME et al. 1999 Mar (PMID:10079102);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 5
6.5
Tsuji S et al. 1987 Mar 5 (PMID:2880291); Kolodny EH et al. 1990 Aug (PMID:2117855); Grace ME et al. 1997 May 15 (PMID:9153297); Montfort M et al. 2004 Jun (PMID:15146461); Haverkaemper S et al. 2011 Apr 1 (PMID:21455010);
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 2
2
2
Pentchev PG et al. 1973 Aug 10 (PMID:4768898); Boer DEC et al. 2020 Mar 9 (PMID:32182893);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1
1
1
Panicker LM et al. 2012 Oct 30 (PMID:23071332);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 2 4
Liu Y et al. 1998 Mar 3 (PMID:9482915);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4 1
4
Barton NW et al. 1991 May 23 (PMID:2023606);
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2 1 1
Panicker LM et al. 2012 Oct 30 (PMID:23071332);
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
06/24/2020
EXPERT CURATION (DATE)
Definitive
06/24/2020
EVIDENCE SUMMARY
The relationship between GBA and Gaucher disease, an autosomal recessive condition that is the most common lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of June 20, 2020. GBA encodes the lysosomal enzyme glucocerebrosidase (glucosylceramidase) which breaks down the glycosphingolipid, glucocerebroside (glucosylceramide). The presence of Gaucher cells (macrophages filled with glucocerebroside) in the spleen, liver, and bone marrow of affected individuals is a distinguishing histological features of this disorder. Gaucher disease is multisystem disease characterized by hepatosplenomegaly, hematological abnormalities, bone disease, and neurological abnormalities. Historically, the disorder has been subclassified as type 1, the non-neuronopathic variant; type 2, the acute neuronopathic variant; type 3, the subacute neuronopathic variant and the collodion baby or neonatal variant (Sidransky 2004, PMID 15464415). Biallelic variants in GBA were first reported in patients with Gaucher disease in 1987 (Tsuji et al). Since then, over 200 variants have been reported. The mechanism of disease is loss of function. There is a clear genotype/phenotype correlation for some variants. For example, the mild p.Asn409Ser variant (formerly known as N370S) is found only in patients with type 1 disease, while p.Leu483Pro (formerly known as L444P) is associated with the neuronal subtypes. Molecular analysis of GBA is complicated by the presence of a highly homologous pseudogene, GBAP. In addition, the traditional variant nomenclature did not include the first 39 amino acids of the protein. These are now included based on the HGVS-recommended nomenclature. The four most common variants account for approximately 90% of the pathogenic variants in the Ashkenazi Jewish population and about 50-60% of pathogenic variants in non-Jewish populations (GeneReviews). These variants are c.84dupG (formerly known as 84GG), c.115+1G>A (formerly known as IVS2+1), p.Asn409Ser (formerly known as p.N370S), p.Leu483Pro (formerly known as p.L444P). Evidence supporting this gene-disease relationship includes case-level and experimental data. Ten unique variants (missense, nonsense, frameshift, splice site) from 13 probands in 9 publications were curated (Tsuji et al, 1987, PMID 2880291; Kolody et al, 1990, PMID 2117855; Beutler et al, 1991, PMID 1961718; He et al, 1992, PMID 1415223; Grace et al, 1997, PMID 9153297; Grace et al, 1999, PMID 10079102; Montfort et al, 2004, PMID 15146461; Haverkaemper et al, 2011, PMID 21455010; Beaujot et al, 2013, PMID 23749476). More information is available in the literature but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is also supported by the function of the gene product, glucocerebrosidase, which is consistent with the clinical features observed in patients with Gaucher disease (Pentchev et al, 1973, PMID 4768898; Boer et al, 2020, PMID 32182893), studies of induced pluripotent stem cells (iPSCs) derived from patients with Gaucher disease and differentiated into macrophages and neurons (Panicker et al, 2012, PMID 23071332), mouse models with variants corresponding to those found in human patients (Liu et al, 1999, PMID 9482915), the impact of culturing iPSCs from patients with Gaucher disease with recombinant glucocerebrosidase (Panicker et al, 2012, PMID 23071332), and the improvement in clinical symptoms in patients treated with enzyme replacement therapy (Barton et al, 1991; PMID 2023606). More information is available in the literature but the maximum score for experimental evidence (6 points) has been reached. In summary, GBA is definitively associated with Gaucher disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity classification was approved by the General GCEP on June 24, 2020. This clinical validity assessment includes data curated by Myriad Women’s Health. LUMPING AND SPLITTING: Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism AND inheritance pattern for Gaucher disease type I (MIM# 230800), type 2 (MIM# 230900), type 3 (MIM# 231000), type IIIc (231005), or perinatal lethal Gaucher disease (MIM# 608013). While these disease entities represent a wide range of clinical severity, the molecular mechanism is loss of function and the inheritance pattern is autosomal recessive for them all. Therefore, these disease entities have been lumped into one disease entity, Gaucher disease. We found differences in the inheritance pattern and phenotypic variability for risk of isolated late-onset Parkinson disease (MIM# 168600) and Lewy body dementia (MIM# 127750). While Parkinson disease and Lewy body dementia may occur at higher rates in individuals with Gaucher disease, Gaucher disease is associated with multi-system disease, as opposed to the increased risk of these isolated conditions occurring in individuals who are heterozygous for variants in GBA. Therefore, these disease entities are not included in this curation and may be curated for GBA at a later date.