The variant c.1504C>T (p.Arg502Cys) substitutes a conserved arginine at the domain 2:3 interface of glucocerebrosidase, a position demonstrated to be critical for enzyme function.1 A different missense change at the same residue, p.Arg502Pro, produces a catalytically dead enzyme (CRIM SA = 0.01), establishing that amino acid substitutions at this position abrogate GCase activity.2 The variant has been reported in patients with Gaucher disease, including one homozygous individual with type 1 GD presenting with hepatosplenomegaly, anemia, and severe bone disease.3 The variant is present at very low frequency in gnomAD (v2.1 AF = 0.0067%, 19/282,556 alleles; v4.1 AF = 0.023%, 370/1,612,378 alleles) with no homozygotes observed.4 REVEL in silico prediction score of 0.817 supports a deleterious effect, consistent with the substitution of a basic arginine with a cysteine at a structurally critical domain interface.5 Classified as Pathogenic by 20 clinical diagnostic laboratories in ClinVar (Variation ID: 4295), reflecting broad clinical consensus.6
GBA1
Final classification
Likely Pathogenic
GBA1 c.1504C>T · p.Arg502Cys
GBA1
The variant c.1504C>T (p.Arg502Cys) substitutes a conserved arginine at the domain 2:3 interface of glucocerebrosidase, a position demonstrated to be critical for enzyme function.
ClinGen Parkinson's Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GBA1 Version 1.0 v1.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 supporting, PM5 moderate, PP3 supporting, PP5 supporting; combination = 2 moderate + 3 supporting, which maps to Likely Pathogenic.
Classification rationale
PM1PM2PM5PP3PP5
Likely Pathogenic
GBA1 c.1504C>T
PM1 + PM2 + PM5 + PP3 + PP5
→
Likely Pathogenic
Gene diagram
· NM_000157.4 · variants mapped to exon structure
GBA1
NM_000157.4
Fetching transcript structure from UCSC…
Applied criteria · 5 applied · 16 assessed
Applied · 5
Strength
Supporting
Moderate
Strong
Very strong
✓
PM1
moderate
Pathogenic
The variant substitutes arginine 502, located at the domain 2:3 interface of glucocerebrosidase. Liou et al. (2006, PMID:16293621) demonstrated that substitution at this exact residue (R463P / p.Arg502Pro) abolishes catalytic activity (CRIM SA = 0.01, dead enzyme), indicating this position is critical for GCase function. The variant maps to a structurally defined interface region essential for enzymatic activity. Additionally, exon 10 of GBA is a recognized mutational hot spot (Ankleshwaria et al., 2014, PMID:24522292).
Arg502 located at domain 2:3 interface of GCase. R502P at same residue produces dead enzyme (Liou et al.2006). Exon 10 is a mutational hot spot in GBA (Ankleshwaria et al.2014).
✓
PM2
supporting
Pathogenic
The variant is present at very low frequency in population databases: gnomAD v2.1 AF = 0.0067% (19/282,556 alleles, 0 homozygotes) and gnomAD v4.1 AF = 0.023% (370/1,612,378 alleles, 0 homozygotes). Both frequencies are below the 0.1% PM2 threshold. The absence of homozygotes is consistent with a recessive disease model. However, 370 alleles in v4.1 tempers the strength to supporting rather than moderate.
gnomAD v2.1 AF 0.0067%19/282556 alleles
✓
PM5
moderate
Pathogenic
A different missense change at the same amino acid residue, p.Arg502Pro (R463P in older nomenclature), has been reported as a pathogenic variant in Gaucher disease. Liou et al. (2006, PMID:16293621) expressed and characterized R463P in a baculovirus/insect cell system and found it is a catalytically dead enzyme (CRIM SA = 0.01). This demonstrates that missense alterations at position Arg502 yield a deleterious effect, satisfying the PM5 requirement for a pathogenic missense change at the same residue.
R463P (p.Arg502Pro) at same codon produces catalytically dead enzyme (CRIM SA = 0.01)establishing pathogenicity of missense changes at this position (Liou et al.2006).
✓
PP3
supporting
Pathogenic
Multiple in silico predictors support a deleterious effect. REVEL score is 0.817 (above the 0.75 damaging threshold). The substitution of a basic arginine with a cysteine capable of forming aberrant disulfide bonds at a position within the domain 2:3 interface of GCase is consistent with a deleterious structural impact. SpliceAI predicts no splicing impact (max delta = 0.06).
REVEL = 0.817 (damaging). BayesDel = 0.469 (borderline). SpliceAI max delta = 0.06 (no splicing impact). Arginine to cysteine substitution at domain interface.
✓
PP5
supporting
Pathogenic
This variant is classified as Pathogenic in ClinVar (Variation ID: 4295) by 20 clinical laboratories. Although the review status is criteria provided, single submitter (1-star, not expert panel reviewed), the broad consensus across multiple independent clinical diagnostic laboratories supports applying PP5 at supporting strength. The variant has been consistently reported as Pathogenic with validated PMID evidence trails.
ClinVar Variation ID 4295: Pathogenic20 clinical laboratoriesreview status criteria provided
Assessed · not applied
Pathogenic
PS2
De novo occurrence data (maternity/paternity confirmed) are not available for this variant in any reviewed source.
PS3
No experimental functional data directly testing NM_000157.4:c.1504C>T (p.Arg502Cys) were identified.
PS4
The variant has been observed in Gaucher disease patients (Ankleshwaria et al., 2014, PMID:24522292 identified one homozygous patient among 33 Indian GD patients), but this is a single observational report without case-control comparison.
PM6
No de novo occurrence data (maternity/paternity confirmed) are available for this variant.
PP1
No co-segregation data with disease in multiple affected family members are available.
PP2
Insufficient gene-level constraint data to apply PP2.
PP4
No patient-specific phenotype or clinical data for the proband are available in this case for evaluation under PP4.
Benign
BA1
Allele frequency in gnomAD is far below the 1% BA1 threshold (v2.1 AF = 0.0067%, v4.1 AF = 0.023%).
BS1
Allele frequency in gnomAD is far below the 0.3% BS1 threshold (v2.1 AF = 0.0067%, v4.1 AF = 0.023%).
BS2
No data on observation of this variant in a healthy adult individual in trans with a known pathogenic GBA1 variant.
BS3
No well-established functional studies demonstrate a benign effect for this variant.
BS4
No segregation data in affected families are available to evaluate lack of segregation with disease.
BP2
No data on observation of this variant in trans with a known pathogenic GBA1 variant in an individual without disease.
BP4
Multiple lines of computational evidence support a deleterious effect rather than a benign one.
BP5
No data on an alternate molecular basis for disease in a case where this variant was also observed.
BP6
No reputable source reports this variant as benign.
N/A · 5
PVS1 · PS1 · BP1 · BP3 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000229475; MAF= 0.02295%, 370/1612378 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00029674; MAF= 0.02967%, 350/1179482 alleles, homozygotes = 0); grpmax FAF= 0.00027066.
v2.1
This variant is present in gnomAD v2.1 (AF= 6.72433e-05; MAF= 0.00672%, 19/282556 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000108632; MAF= 0.01086%, 14/128876 alleles, homozygotes = 0); grpmax FAF= 7.443e-05.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.023%
· 370 / 1,612,378
0 hom · FAF 0.027%
0 hom · FAF 0.027%
European (non-Finnish) 350 / 1,179,482 |
0.03% |
Remaining individuals 6 / 62,450 |
0.0096% |
African/African American 6 / 74,490 |
0.0081% |
South Asian 7 / 90,922 |
0.0077% |
Admixed American 1 / 59,782 |
0.0017% |
+ 5 not observed (European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish)
gnomAD v2.1
0.0067%
· 19 / 282,556
0 hom · FAF 0.0074%
0 hom · FAF 0.0074%
European (non-Finnish) 14 / 128,876 |
0.011% |
South Asian 3 / 30,616 |
0.0098% |
African/African American 2 / 24,964 |
0.008% |
+ 5 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (20 clinical laboratories). (ClinVarID = 4295)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.817. BayesDel score = 0.468641.
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 6 further PMIDs triaged but not cited — see Sources & References.
Analyses of variant acid beta-glucosidases: effects of Gaucher disease mutations.
Searched
R463CR502CArg502CysArg463Cysc.1504C>T1504
Found
Characterized 52 GCase missense variants in a baculovirus/insect cell expression system. R463P (p.Arg502Pro, a different missense substitution at the same codon as c.1504C>T) produced a catalytically dead enzyme with CRIM SA of 0.01. The variant p.Arg502Cys (R463C) was not tested in this study.
Variant
◇ Residue / gene-level — variant not named
Applied to
→PM1 supports · met
→PM5 supports · met
Why
R463P at the same residue as R463C/R502C is a dead enzyme, establishing that Arg502 is critical for GCase function. Referenced in PM1 (domain-level evidence) and PM5 (different pathogenic missense at same residue).
Only M416V and R463P completely inactivate the enzyme.
Location Table 1 (R463P entry), Results, Discussion section · Context Baculovirus/Sf21 insect cell expression system. CRIM specific activity, CBE inhibition, deoxynojirimycin Ki, phosphatidylserine activation, cathepsin D sensitivity assays. · full text
Novel mutations in the glucocerebrosidase gene of Indian patients with Gaucher disease.
Searched
R463Cc.1504C>Tc.15041504
Found
Identified R463C (c.1504C>T, same variant using older protein numbering) in one homozygous Indian Gaucher disease patient among 33. The patient had type 1 GD with hepatosplenomegaly, severe bone osteomyelitis of femur, chronic anemia, and prior splenectomy. L444P was the most common mutation in the cohort.
Variant
✓ Names this variant — characterised directly
Applied to
→PM1 supports · met
Why
Variant confirmed in a Gaucher disease patient. Referenced in PM1 (exon 10 hot spot context) and PS4 (single observation, insufficient for statistical enrichment).
R463C homozygous mutation was seen in one patient (3.03%) with type 1 GD with severe bone osteomylitis of femur, hepatosplenomegaly and chronic anemia, and splenectomy was carried out because of severely enlarged spleen.
Location Abstract, Results, Table 2 (Patient 3), Discussion · full text
Sources & reference links
9Sources
Triaged references · 6 PMIDs not cited in assessment
21704274 ↗
Identification of recombinant alleles using quantitative real-time PCR implications for Gaucher disease.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
32165122 ↗
High risk screening for Gaucher disease in patients with splenomegaly and/or thrombocytopenia in China: 55 cases identified.
CLINVAR
8294487 ↗
Analysis of human acid beta-glucosidase by site-directed mutagenesis and heterologous expression.
CLINVAR
10796875 ↗
Analysis and classification of 304 mutant alleles in patients with type 1 and type 3 Gaucher disease.
CLINVAR