NM_000157.4:c.1495G>C

GBA1 · NP_000148.2:p.(Val499Leu) · NM_000157.4

GRCh37: chr1:155204996 C>G · GRCh38: chr1:155235205 C>G

Gene: GBA1 Transcript: NM_000157.4

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

GBA1

Transcript

NM_000157.4

Protein

NP_000148.2:p.(Val499Leu)

gnomAD AF

4.153699272172695e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000157.4:c.1495G>C (p.Val499Leu) is a missense variant in GBA1, which encodes the lysosomal enzyme glucocerebrosidase. Biallelic pathogenic variants in GBA1 cause Gaucher disease (autosomal recessive); heterozygous variants are associated with increased risk for Parkinson disease.

This variant is present at extremely low frequency in population databases: gnomAD v2.1 allele frequency = 0.0052% (13/251,170 alleles, 0 homozygotes) and gnomAD v4.1 allele frequency = 0.0042% (67/1,613,020 alleles, 0 homozygotes), meeting PM2_Supporting.

In silico analysis supports a deleterious effect: the REVEL meta-predictor score is 0.733, exceeding the commonly used threshold of 0.5. SpliceAI predicts no splicing impact (max delta = 0.00). The BayesDel score (0.348) is below threshold, resulting in partially conflicting computational evidence; PP3 is applied at the supporting level.

This variant has been reported in ClinVar (Variation ID 634558) with conflicting classifications: Uncertain significance (2 clinical laboratories), Likely pathogenic (2 clinical laboratories), and Likely benign (1 clinical laboratory). No ClinGen expert panel classification is available.

Functional studies referenced in the literature (PMID:10714667, PMID:12924289) suggest reduced glucocerebrosidase activity for the mature protein equivalent V460L, but full-text verification of these studies was not available at the time of assessment. PS3 is not assessed pending direct review of primary data.

The ClinGen Parkinson's Disease Expert Panel specification for GBA1 (v1.0.0) is an unstructured ruleset without specific criterion thresholds. The assessment therefore applies generic ACMG/AMP 2015 criteria (PMID:25741868).

Overall, the evidence applied includes PM2_Supporting and PP3_Supporting. No benign criteria were met. All remaining criteria (PVS1, PS1-PS5, PM1, PM5-PM6, PP1-PP2, PP4-PP5, BA1, BS1-BS4, BP1-BP2, BP4-BP7) were either not met, not assessed, or not applicable.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	PVS1 is not applicable to missense variants. This variant (c.1495G>C, p.Val499Leu) does not fall into any of the generic PVS1 null-variant buckets (nonsense, frameshift, canonical ±1,2 splice consensus, initiation codon, single/multi-exon deletion).	pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	PS1 requires a different nucleotide change at the same codon resulting in the same amino acid change (p.Val499Leu) with established pathogenicity. No such comparator variant with definitive pathogenic classification was identified in the evidence pipeline.
PS2	Not met	PS2 requires a de novo occurrence with confirmed maternity and paternity. No de novo data were identified for this variant. GBA1-related Gaucher disease is autosomal recessive; de novo heterozygous occurrences are not consistent with the established disease mechanism.
PS3	Not assessed	The exploratory evidence pipeline identified functional studies (PMID:10714667 Koprivica et al. 2000; PMID:12924289 Ronan et al. 2003) reporting reduced glucocerebrosidase activity for the mature protein equivalent V460L (p.Val499Leu). However, full-text articles for these PMIDs are not available in the case directory and could not be directly verified for variant-specific evidence. Without direct confirmation of assay methodology, effect magnitude, and variant identity in the full text, PS3 cannot be applied.
PS4	Not met	PS4 requires statistically significant enrichment of the variant in affected individuals compared to controls. While this variant has been reported in Gaucher disease probands and ClinVar contains multiple submissions, no published case-control study with calculated odds ratio is available. The gnomAD population frequency is very low (AF ~0.005%), which provides context but does not by itself satisfy PS4 without a formal case-control comparison.	clinvar gnomad_v2 gnomad_v4
PS5	Not assessed	PS5 requires a pathogenic variant at the same codon from a reputable source. No such variant was identified for codon 499 (Val) of GBA1 through the evidence pipeline.
PM1	Not met	PM1 requires location in a mutational hotspot or critical functional domain without benign variation. The GBA1 ClinGen Parkinson's Disease VCEP (v1.0.0) does not define a PM1 domain or hotspot. Although the variant lies within the catalytic domain of glucocerebrosidase, no statistical evidence of pathogenic variant clustering or formal VCEP-defined hotspot is available.	cspec
PM2	Met	This variant is present at extremely low frequency in population databases: gnomAD v2.1 allele frequency = 5.18e-05 (13/251,170 alleles, 0 homozygotes, grpmax FAF = 5.60e-05) and gnomAD v4.1 allele frequency = 4.15e-05 (67/1,613,020 alleles, 0 homozygotes, grpmax FAF = 3.75e-05). Both are well below the 0.1% PM2 threshold. The variant is absent from gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 requires a different pathogenic missense change at the same amino acid residue. The automated PM5 candidate harvest (pm5_candidates.json) was unable to identify same-residue comparator variants. No pathogenic variant at GBA1 residue 499 (Val) with a different amino acid substitution was identified.	pm5_candidates
PM6	Not met	PM6 requires a de novo occurrence with confirmed maternity and paternity. No de novo data were identified for this variant. Gaucher disease is autosomal recessive, making de novo heterozygous occurrences inconsistent with the established disease mechanism.
PP1	Not met	PP1 requires cosegregation with disease in multiple affected family members. No systematic segregation analysis with sufficient informative meioses or LOD scores was identified for this variant. Limited family-based observations mentioned in exploratory sources are insufficient to meet PP1.
PP2	Not met	PP2 requires a low rate of benign missense variation in the gene and that missense variants are a common mechanism of disease. While missense variants are a well-established mechanism for Gaucher disease, no gene-specific benign missense constraint data (e.g., Z-score, missense constraint metrics) were available to demonstrate a low rate of benign missense variation in GBA1.
PP3	Met	Multiple lines of computational evidence support a deleterious effect. The REVEL meta-predictor score is 0.733, which exceeds the commonly used threshold of 0.5 for predicting pathogenicity. SpliceAI predicts no splicing impact (max delta = 0.00), which is neutral for this criterion. The BayesDel score is 0.348 (below the 0.5 threshold), but the REVEL score provides sufficient in silico support at the supporting level.	revel bayesdel spliceai
PP4	Not met	PP4 requires that the patient's phenotype or family history is highly specific for the disease. No patient-specific phenotypic or family history data were available for this assessment.
PP5	Not met	PP5 requires that a reputable source has classified the variant as pathogenic. ClinVar (Variation ID 634558) reports conflicting classifications: Uncertain significance (2 clinical laboratories), Likely pathogenic (2 clinical laboratories), and Likely benign (1 clinical laboratory). No ClinGen expert panel classification is available. The conflicting ClinVar submissions and absence of expert panel consensus preclude application of PP5.	clinvar
BA1	Not met	BA1 requires allele frequency >1% in population databases. This variant has an allele frequency of approximately 0.005% in gnomAD (v2.1: 5.18e-05; v4.1: 4.15e-05), which is far below the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	BS1 requires allele frequency >0.3% in population databases. This variant has an allele frequency of approximately 0.005% in gnomAD (v2.1: 5.18e-05; v4.1: 4.15e-05), which is far below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	BS2 requires observation in a healthy adult in the homozygous state for a recessive disorder. This variant has zero homozygotes observed in gnomAD v2.1 (0/251,170) and gnomAD v4.1 (0/1,613,020). No evidence of homozygous healthy adults is available.	gnomad_v2 gnomad_v4
BS3	Not met	BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect. The available functional evidence (exploratory results referencing PMID:10714667 and PMID:12924289) indicates reduced glucocerebrosidase activity for the mature protein equivalent V460L, which is consistent with a damaging — not benign — effect. BS3 is therefore not applicable.
BS4	Not met	BS4 requires lack of segregation in affected family members. No evidence of non-segregation was identified. The limited available evidence suggests cosegregation with disease rather than non-segregation.
BP1	Not met	BP1 applies to missense variants in genes where primarily truncating variants cause disease. In GBA1, both missense and truncating variants are well-established causes of Gaucher disease. Missense variants are a primary disease mechanism, not an exception. BP1 does not apply.
BP2	Not met	BP2 requires observation in trans with a pathogenic variant for a dominant disorder, or in cis with a pathogenic variant in a recessive disorder in an unaffected individual. No phasing data are available for this variant, and given its extremely low frequency, such observations are unlikely to exist in current databases.
BP3	N/A	Skipped per instructions. BP3 applies to in-frame deletions/insertions in repetitive regions; this is a missense substitution.
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact on gene product. The REVEL meta-predictor score is 0.733, which strongly suggests a deleterious effect — directly contradicting BP4. BayesDel (0.348) is below 0.5, and SpliceAI delta is 0.00, but REVEL's prediction of damaging effect precludes application of BP4.	revel bayesdel spliceai
BP5	Not met	BP5 requires that the variant is found in a case with an alternate molecular basis for disease. No such evidence was identified.
BP6	Not met	BP6 requires that a reputable source classifies the variant as benign. ClinVar reports conflicting classifications (US, LP, LB). One submitter classified as Likely benign, but the overall ClinVar classification is Uncertain significance, and no ClinGen expert panel has classified as benign. BP6 is not met.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splicing impact. This variant (c.1495G>C, p.Val499Leu) is a missense (non-synonymous) substitution and is not eligible for BP7.

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