NM_000157.4:c.1504C>T

GBA1 · NP_000148.2:p.(Arg502Cys) · NM_000157.4

GRCh37: chr1:155204987 G>A · GRCh38: chr1:155235196 G>A

Gene: GBA1 Transcript: NM_000157.4

Final call

Likely Pathogenic

PM1 moderate PM2 supporting PM5 moderate PP3 supporting PP5 supporting

Variant details

Gene

GBA1

Transcript

NM_000157.4

Protein

NP_000148.2:p.(Arg502Cys)

gnomAD AF

0.00022947472614982342 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_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.	pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 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.
PS2	Not assessed	De novo occurrence data (maternity/paternity confirmed) are not available for this variant in any reviewed source.
PS3	Not met	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.	PMID:16293621
PS4	Not met	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.	PMID:24522292
PS5	Not assessed	PS5 is not applicable as no established segregation or phenotype data beyond what is evaluated under other criteria is available for independent assessment.
PM1	Met	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).	PMID:16293621 PMID:24522292
PM2	Met	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 gnomad_v4
PM5	Met	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.	PMID:16293621
PM6	Not assessed	No de novo occurrence data (maternity/paternity confirmed) are available for this variant.
PP1	Not assessed	No co-segregation data with disease in multiple affected family members are available.
PP2	Not met	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.
PP3	Met	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 spliceai bayesdel
PP4	Not assessed	No patient-specific phenotype or clinical data for the proband are available in this case for evaluation under PP4.
PP5	Met	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
BA1	Not met	Allele frequency in gnomAD is far below the 1% BA1 threshold (v2.1 AF = 0.0067%, v4.1 AF = 0.023%).	gnomad_v2 gnomad_v4
BS1	Not met	Allele frequency in gnomAD is far below the 0.3% BS1 threshold (v2.1 AF = 0.0067%, v4.1 AF = 0.023%).	gnomad_v2 gnomad_v4
BS2	Not assessed	No data on observation of this variant in a healthy adult individual in trans with a known pathogenic GBA1 variant.
BS3	Not met	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.	PMID:16293621
BS4	Not assessed	No segregation data in affected families are available to evaluate lack of segregation with disease.
BP1	N/A	GBA1 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.
BP2	Not assessed	No data on observation of this variant in trans with a known pathogenic GBA1 variant in an individual without disease.
BP3	N/A	Skipped per instruction. BP3 applies to in-frame deletions/insertions in non-repeat regions, not missense substitutions.
BP4	Not met	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.	revel spliceai bayesdel
BP5	Not assessed	No data on an alternate molecular basis for disease in a case where this variant was also observed.
BP6	Not met	No reputable source reports this variant as benign. ClinVar consensus is Pathogenic (Variation ID: 4295, 20 clinical laboratories).	clinvar
BP7	N/A	NM_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.

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