LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-05
Case ID: NM_000157.4_c.1448T_C_20261105_011745
Framework: ACMG/AMP 2015
Variant classification summary

NM_000157.4:c.1448T>C

GBA1  · NP_000148.2:p.(Leu483Pro)  · NM_000157.4
GRCh37: chr1:155205043 A>G  ·  GRCh38: chr1:155235252 A>G
Gene: GBA1 Transcript: NM_000157.4
Final call
Pathogenic
PS1 strong PS3 supporting PS4 strong PM3 moderate PP3 moderate BP2 supporting benign
All criteria require review: For research and educational purposes only.
Variant details
Gene
GBA1
Transcript
NM_000157.4
Protein
NP_000148.2:p.(Leu483Pro)
gnomAD AF
9.857518558793589e-05 (v4.1)
ClinVar
Pathogenic
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PS1 strong reflects the established GBA1 Leu483Pro/L444P disease mutation.
2
Pathogenic: PS3 supporting reflects deficient glucocerebrosidase activity and absent or markedly reduced protein associated with L444P.
3
Pathogenic: PS4 strong reflects 12/144 cases versus 0/100 controls, with OR 18.96 and a confidence interval excluding 1.
4
Pathogenic: PM3 moderate reflects L444P in trans with the disease-associated 5958T variant in an affected patient.
5
Pathogenic: PP3 moderate reflects REVEL 0.858, above the calibrated moderate threshold of 0.773.
6
No benign classification: BP2 supporting benign is a single supporting benign criterion and does not satisfy a benign rule alone.
Final determination: Under generic ACMG/AMP 2015 fallback rules, two strong pathogenic criteria (PS1 and PS4) satisfy the Pathogenic combination rule; the single supporting benign criterion BP2 does not satisfy a benign rule.
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 Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Met Met: the exact Leu-to-Pro substitution is an established Gaucher disease mutation in multiple reports, with SpliceAI maximum delta 0.002 indicating no significant splice impact.
PMID:8929950 PMID:24126159 PMID:1972019 PMID:1899336 spliceai
PS2 Not assessed Not assessed: no documented affected proband has a de novo variant with both maternity and paternity confirmed.
clinvar
PS3 Met Met at supporting strength: L444P-associated cells showed deficient glucocerebrosidase activity and absent protein, but complex-allele confounding prevents strong PS3 application.
PMID:8929950 PMID:1972019 PMID:1899336
PS4 Met Met: p.L444P occurred in 12/144 cases versus 0/100 controls, with continuity-corrected OR 18.96 (95% CI 1.11-324.11), exceeding the >5.0 threshold and excluding 1.
PMID:24126159
PM1 Not assessed Not assessed: no authoritative GBA1 domain table, validated hotspot route, or region-specific benign-variation evidence establishes the PM1 requirement.
cspec hotspots
PM2 Not met Not met: gnomAD v4.1 grpmax FAF is 0.00019859, above the <=0.0001 PM2 cutoff, and v2.1 is higher at 0.00119554.
gnomad_v2 gnomad_v4 PMID:25741868
PM3 Met Met: MSM61 carried L444P and 5958T on separate alleles, providing phase-resolved evidence of the queried variant in trans with another disease-associated GBA1 variant.
PMID:1899336
PM4 N/A Not applicable: PM4 requires a protein-length change, and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Not assessed Not assessed: no different pathogenic missense variant at residue 483 was identified for comparison with Leu483Pro.
pm5_candidates
PM6 Not assessed Not assessed: a ClinVar de novo label lacks an affected proband, clinical condition, and supporting parental-testing details.
clinvar
PP1 Not assessed Not assessed: affected siblings shared p.L444P, but available reports do not establish qualifying segregation in a definitively disease-causing context.
PMID:24126159 PMID:8929950
PP2 Not assessed Not assessed: the case lacks gene-wide benign-missense-rate data and a complete GBA1 missense-mechanism assessment required by PP2.
gnomad_v4 PMID:1899336
PP3 Met Met, moderate: missense REVEL 0.858 exceeds the PP3 moderate threshold of >=0.773.
revel
PP4 Not assessed Not assessed: the available patient record lacks a phenotype or family-history description sufficiently specific for a single-genetic-etiology disease.
PP5 Not met Not met: ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic classification, only non-expert submissions and aggregate labels.
clinvar
BA1 Not met Not met: gnomAD v2.1 grpmax FAF is 0.00119554, far below the >=0.05 BA1 threshold.
gnomad_v2 gnomad_v4 clinvar PMID:25741868
BS1 Not met Not met: the highest filtering FAF is 0.00119554, below the 0.01 default, and no validated GBA1 maximum-credible-frequency threshold is available.
gnomad_v2 gnomad_v4
BS2 Not met Not met: gnomAD reports zero homozygotes in v2.1 and v4.1, and heterozygous GBA1 Parkinson risk is late-onset and reduced penetrance.
gnomad_v2 gnomad_v4
BS3 Not assessed Not assessed: no study demonstrates normal GBA1 function or splicing for p.Leu483Pro; available reports instead show deficient activity or inconclusive complex-allele results.
PMID:8929950 PMID:1972019 PMID:1899336
BS4 Not assessed Not assessed: no affected family members are documented as lacking the variant, so non-segregation cannot be evaluated.
BP1 Not met Not met: multiple established GBA1 missense disease alleles are documented, so the gene is not supported as primarily truncation-driven by the supplied evidence.
PMID:1899336 PMID:1972019 PMID:24126159
BP2 Met Met: the reported complex allele placed L444P with A456P and V460V in cis in an affected fetus with severe type 2 Gaucher disease.
PMID:8929950
BP3 N/A Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Not met Not met: missense REVEL 0.858 is above the BP4 supporting threshold of <=0.29.
revel
BP5 Not assessed Not assessed: no documented patient-level alternate molecular basis is available for a case carrying this variant.
BP6 Not met Not met: ClinVar contains no exact-variant expert-panel Benign or Likely benign classification required for BP6.
clinvar
BP7 N/A Not applicable: BP7 requires a synonymous variant, and this is a missense variant.
generic_acmg_combination_rules
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