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.
gnomad_v2 ↗ gnomad_v4 ↗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.
spliceai ↗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.
clinvar ↗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).
cspec ↗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.
