0%
GBA1c.1504C>TLikely pathogenic
Print report
Variant interpretation report

GBA1 c.1504C>T, p.(Arg502Cys)

NM_000157.4:c.1504C>T NP_000148.2:p.(Arg502Cys) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About GBA1

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is ClinGen GBA1 VCEP v1.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 5 Benign evidence criteria: 0
Pathogenic criteria applied · 5
PM1Moderate
PM1 · moderate

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).

PM2Supporting
PM2 · supporting

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.

PM5Moderate
PM5 · moderate

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.

PP3Supporting
PP3 · supporting

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).

PP5Supporting
PP5 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
370 / 1,612,378 alleles

gnomAD v4.1: 370 / 1,612,378 alleles. Recorded AF 0.000229475. Recorded homozygote count 0.

gnomAD 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.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.060 maximum delta

Recorded SpliceAI maximum delta score: 0.060. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗
ClinVar submissions
20 reported laboratory submissions

20 Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Applied · PP5 → ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen GBA1 VCEP v1.0, with the data and sources behind each one.

27 criteria with recorded statuses: 5 met · 8 not met · 9 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

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.

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.

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.

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.

Classified as Pathogenic by 20 clinical diagnostic laboratories in ClinVar (Variation ID: 4295), reflecting broad clinical consensus.

Met · 5

PM1 ModerateThe 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). Details ▾Hide ▴
Evidence considered
  • 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).
Still missing
  • Cancerhotspots.org does not flag this residue as statistically significant for somatic mutations.
Sources
PMID:16293621 ↗PMID:24522292 ↗
PM2 SupportingThe 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF 0.0067%
  • 19/282
  • 556 alleles
  • 0 homozygotes. gnomAD v4.1 AF 0.023%
  • 370/1
  • 612
  • 378 alleles
  • 0 homozygotes. Both below 0.1% threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
PM5 ModerateA 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. Details ▾Hide ▴
Evidence considered
  • 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).
Still missing
  • R463P is not listed in ClinVar as a separate submission with expert panel classification
  • evidence is from functional characterization in a single publication.
Sources
PMID:16293621 ↗
PP3 SupportingMultiple 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). Details ▾Hide ▴
Evidence considered
  • REVEL = 0.817 (damaging). BayesDel = 0.469 (borderline). SpliceAI max delta = 0.06 (no splicing impact). Arginine to cysteine substitution at domain interface.
Still missing
  • BayesDel score (0.469) is borderline and provides weaker support than REVEL.
Sources
revelspliceai ↗bayesdel
PP5 SupportingThis 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. Details ▾Hide ▴
Evidence considered
  • ClinVar Variation ID 4295: Pathogenic
  • 20 clinical laboratories
  • review status criteria provided
  • single submitter (1-star). Broad clinical consensus.
Still missing
  • No ClinGen expert panel classification
  • review status is 1-star rather than 3-star.
Sources
clinvar ↗

Not met · 8 · evaluated, threshold not reached

PS3 No experimental functional data directly testing NM_000157.4:c.1504C>T (p.Arg502Cys) were identified. Liou et al. (2006, PMID:16293621) characterized R463P (p.Arg502Pro), a different amino acid substitution at the same codon, and found it produces a catalytically dead enzyme (CRIM SA = 0.01). However, testing of a different missense change at the same position constitutes PM1/PM5 evidence, not variant-specific PS3 functional evidence. No systematic range characterization study (saturation mutagenesis, tiling screen, systematic truncation series) spanning position 502 was identified. Details ▾Hide ▴
Evidence considered
  • Liou et al. (2006) tested R463P (not R463C) at the same codon and found dead enzyme. Different amino acid substitution
  • does not meet PS3 threshold for variant-specific functional evidence.
Still missing
  • No experimental functional data directly testing p.Arg502Cys. No systematic range characterization study that includes position 502.
Sources
PMID:16293621 ↗
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. No statistically significant enrichment in affected individuals versus controls has been demonstrated. Details ▾Hide ▴
Evidence considered
  • Observed in 1/33 GD patients in a single cohort study (Ankleshwaria et al.
  • 2014). No case-control data for statistical enrichment.
Still missing
  • No case-control study demonstrating statistically significant enrichment in affected individuals.
Sources
PMID:24522292 ↗
PP2 Insufficient gene-level constraint data to apply PP2. GBA1 tolerates both pathogenic and benign missense variation, and a formal missense Z-score or constraint analysis was not performed for this assessment. PP2 requires a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. Details ▾Hide ▴
Evidence considered
  • No gene-level missense constraint metric (Z-score
  • o/e
  • missense depletion) analyzed for GBA1.
Still missing
  • Missense constraint metric for GBA1 not evaluated.
BA1 Allele frequency in gnomAD is far below the 1% BA1 threshold (v2.1 AF = 0.0067%, v4.1 AF = 0.023%). Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF 0.0067%
  • v4.1 AF 0.023%. Both far below 1% BA1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 Allele frequency in gnomAD is far below the 0.3% BS1 threshold (v2.1 AF = 0.0067%, v4.1 AF = 0.023%). Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF 0.0067%
  • v4.1 AF 0.023%. Both far below 0.3% BS1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No well-established functional studies demonstrate a benign effect for this variant. The only functional data at this position (R463P/R502P in Liou et al., 2006) supports a deleterious rather than benign effect. Details ▾Hide ▴
Evidence considered
  • No functional studies supporting benign effect. R463P at same position produces dead enzyme (Liou et al.
  • 2006).
Sources
PMID:16293621 ↗
BP4 Multiple lines of computational evidence support a deleterious effect rather than a benign one. REVEL score is 0.817 (damaging), and SpliceAI shows no benign effect on splicing (max delta = 0.06). No computational evidence supports a benign interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL = 0.817 (damaging
  • not benign). BayesDel = 0.469 (not clearly benign). SpliceAI = 0.06 (no evidence for benign splicing rescue).
Sources
revelspliceai ↗bayesdel
BP6 No reputable source reports this variant as benign. ClinVar consensus is Pathogenic (Variation ID: 4295, 20 clinical laboratories). Details ▾Hide ▴
Evidence considered
  • ClinVar consensus is Pathogenic
  • not benign. No source reports as benign.
Sources
clinvar ↗

Not assessed · 9 · no assessment recorded

PS2 De novo occurrence data (maternity/paternity confirmed) are not available for this variant in any reviewed source. Details ▾Hide ▴
Evidence considered
  • No de novo data identified in literature or databases reviewed.
Still missing
  • De novo occurrence data unavailable.
PM6 No de novo occurrence data (maternity/paternity confirmed) are available for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo data identified.
Still missing
  • De novo occurrence data unavailable.
PP1 No co-segregation data with disease in multiple affected family members are available. Details ▾Hide ▴
Evidence considered
  • No family co-segregation data identified.
Still missing
  • Co-segregation data unavailable.
PP4 No patient-specific phenotype or clinical data for the proband are available in this case for evaluation under PP4. Details ▾Hide ▴
Evidence considered
  • No patient phenotype data available.
Still missing
  • Proband phenotype data not provided.
BS2 No data on observation of this variant in a healthy adult individual in trans with a known pathogenic GBA1 variant. Details ▾Hide ▴
Evidence considered
  • No data on observation in trans with a pathogenic variant in healthy individuals.
Still missing
  • Data on trans observation in healthy adults not available.
BS4 No segregation data in affected families are available to evaluate lack of segregation with disease. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • Segregation data unavailable.
BP2 No data on observation of this variant in trans with a known pathogenic GBA1 variant in an individual without disease. Details ▾Hide ▴
Still missing
  • Data on trans observation unavailable.
BP5 No data on an alternate molecular basis for disease in a case where this variant was also observed. Details ▾Hide ▴
Evidence considered
  • No alternate molecular basis data available.
Still missing
  • Alternate molecular basis data unavailable.
PS5 PS5 is not applicable as no established segregation or phenotype data beyond what is evaluated under other criteria is available for independent assessment. Details ▾Hide ▴

No further detail was recorded.

Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000157.4:c.1504C>T is a missense variant (p.Arg502Cys), not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). The variant does not meet the ClinGen PVS1 decision tree entry criteria for loss-of-function variants. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • variant bucket other in generic PVS1 framework. Not eligible for PVS1.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PS1 N/APS1 applies when a novel nucleotide change produces the same amino acid change as an established pathogenic variant. The variant under assessment (c.1504C>T, p.Arg502Cys) is itself the established entity referenced in the literature and ClinVar; no novel synonymous nucleotide change leading to p.Arg502Cys is being evaluated. Details ▾Hide ▴
Evidence considered
  • PS1 is not applicable to the index variant being assessed
  • it applies to novel nucleotide changes producing the same amino acid change as a known pathogenic variant.
BP1 N/AGBA1 is associated with Gaucher disease through both missense and truncating pathogenic variants. BP1 applies only when missense variants are not a known disease mechanism for the gene. Details ▾Hide ▴
Evidence considered
  • GBA1 disease mechanism includes both missense and truncating variants.
BP3 N/ASkipped per instruction. BP3 applies to in-frame deletions/insertions in non-repeat regions, not missense substitutions. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ANM_000157.4:c.1504C>T is a missense variant (p.Arg502Cys), not a synonymous or intronic variant. BP7 applies only to synonymous variants without predicted splicing impact. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 applies to synonymous variants.

Identifiers

Gene
GBA1
Transcript
NM_000157.4
Coding (HGVS c.)
NM_000157.4:c.1504C>T
Protein (HGVS p.)
NP_000148.2:p.(Arg502Cys)
GRCh38
chr1:155235196 G>A
GRCh37
chr1:155204987 G>A
ClinVar
4295

Gene diagram

Every interpreted variant in GBA1, mapped onto the exon structure of NM_000157.4. Select a row to find it on the plot.

GBA1NM_000157.4
Fetching transcript structure from UCSC…
gnomAD v4.1 370 / 1,612,378 alleles AF 0.000229 · 0 homozygotes · FAF 0.000271
gnomAD v2.1 19 / 282,556 alleles AF 6.72e-05 · 0 homozygotes · FAF 7.44e-05
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0.00023 · 370 / 1,612,378 alleles · 0 hom · FAF 0.00027
European (non-Finnish)350 / 1,179,482 0.0003
Remaining individuals6 / 62,450 9.6e-05
African/African American6 / 74,490 8.1e-05
South Asian7 / 90,922 7.7e-05
Admixed American1 / 59,782 1.7e-05
0 alternate alleles recorded in 5 other groups: European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish.

gnomAD v2.1

AF 6.7e-05 · 19 / 282,556 alleles · 0 hom · FAF 7.4e-05
European (non-Finnish)14 / 128,876 0.00011
South Asian3 / 30,616 9.8e-05
African/African American2 / 24,964 8e-05
0 alternate alleles recorded in 5 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.

Statements

gnomAD 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.

gnomAD 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.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -75 bp
0.030
SpliceAI acceptor gainat +111 bp
0.010
SpliceAI donor lossat -13 bp
0.060
SpliceAI donor gainat +2 bp
0.000
Pangolin splice lossmagnitude shown
-0.040
Pangolin splice gain
0.010

Other predictors

REVEL
0.817
BayesDel
0.469

How the predictions were used

PP3 SupportingMultiple 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). Details ▾Hide ▴
Evidence considered
  • REVEL = 0.817 (damaging). BayesDel = 0.469 (borderline). SpliceAI max delta = 0.06 (no splicing impact). Arginine to cysteine substitution at domain interface.
Still missing
  • BayesDel score (0.469) is borderline and provides weaker support than REVEL.
Sources
revelspliceai ↗bayesdel
BP4 Multiple lines of computational evidence support a deleterious effect rather than a benign one. REVEL score is 0.817 (damaging), and SpliceAI shows no benign effect on splicing (max delta = 0.06). No computational evidence supports a benign interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL = 0.817 (damaging
  • not benign). BayesDel = 0.469 (not clearly benign). SpliceAI = 0.06 (no evidence for benign splicing rescue).
Sources
revelspliceai ↗bayesdel
BP7 N/ANM_000157.4:c.1504C>T is a missense variant (p.Arg502Cys), not a synonymous or intronic variant. BP7 applies only to synonymous variants without predicted splicing impact. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 applies to synonymous variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.817. BayesDel score = 0.468641.

8 paper records listed. 2 cited in the classification.

Cited in the classification

  • Analyses of variant acid beta-glucosidases: effects of Gaucher disease mutations.
    Liou B et al. · 2006 Feb 17
    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.
    → PM1 → PM5 Does not name this variant
    PMID 16293621 ↗
    Source detail
    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.

  • Novel mutations in the glucocerebrosidase gene of Indian patients with Gaucher disease.
    Ankleshwaria C et al. · 2014 Apr
    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.
    → PM1 Names this variant
    PMID 24522292 ↗
    Source detail
    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

Other recorded publications

  • Sequence of two alleles responsible for Gaucher disease.
    Characterized two novel GBA alleles from Gaucher disease patients using enzymatically amplified RNA transcripts. Described a triple-point mutation allele and a separate point mutation. c.1504C>T was not among the mutations identified.
    Does not name this variant
    PMID 1972019 ↗
  • Identification of recombinant alleles using quantitative real-time PCR implications for Gaucher disease.
    Velayati A et al. · 2011
    Describes quantitative real-time PCR methods for identifying recombinant GBA alleles and their implications for Gaucher disease. The specific variant c.1504C>T (p.Arg502Cys) was not identified in this paper.
    Does not name this variant
    PMID 21704274 ↗
  • 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.
    ACMG/AMP standards and guidelines for the interpretation of sequence variants. Provides the generic classification framework but does not discuss any specific GBA1 variant.
    Does not name this variant
    PMID 25741868 ↗
  • High risk screening for Gaucher disease in patients with splenomegaly and/or thrombocytopenia in China: 55 cases identified.
    High-risk screening study for Gaucher disease in 787 Chinese patients with splenomegaly and/or thrombocytopenia. Identified 44 GBA variants in 55 confirmed GD patients, but c.1504C>T (p.Arg502Cys / R463C) was not among them.
    Does not name this variant
    PMID 32165122 ↗
  • Analysis of human acid beta-glucosidase by site-directed mutagenesis and heterologous expression.
    Site-directed mutagenesis study characterizing 22 Gaucher disease mutations expressed in Sf9 cells. Full text was not available for review (only a screenshot image). Variant-specific confirmation of c.1504C>T could not be independently verified.
    Does not name this variant
    PMID 8294487 ↗
  • Analysis and classification of 304 mutant alleles in patients with type 1 and type 3 Gaucher disease.
    Koprivica V et al. · 2000
    Analysis and classification of 304 mutant GBA alleles in Gaucher disease patients. Full text was not available for review (only a screenshot image). Variant-specific confirmation of c.1504C>T could not be independently verified.
    Does not name this variant
    PMID 10796875 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 370 / 1,612,378 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.060 Open source ↗
ClinVar 20 Pathogenic Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD 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.

gnomAD 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.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

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.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.