LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-11
Case ID: NM_000157.4_c.1093G_A_20260811_124207
Framework: ACMG/AMP 2015
Variant classification summary

NM_000157.4: c.1093G>A

GBA1  · NP_000148.2:p.(Glu365Lys)  · NM_000157.4
GRCh37: chr1:155206167 C>T  ·  GRCh38: chr1:155236376 C>T
Gene: GBA1 Transcript: NM_000157.4
Final call
Benign
BS1 supporting BS2 strong BS4 strong BP2 supporting BP5 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
GBA1
Transcript
NM_000157.4
Protein
NP_000148.2:p.(Glu365Lys)
gnomAD AF
0.012312185426852992 (v4.1)
ClinVar
Benign
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
BS2 (Strong): 196 gnomAD v4.1 homozygotes without Gaucher disease show biallelic carriage of this allele is non-pathogenic.
2
BS4 (Strong): in a Gaucher disease family, E326K did not segregate with disease - affected members lack it while unaffected carriers have it.
3
BS1 (Supporting): gnomAD v4.1 allele frequency 1.23% far exceeds the expected frequency for a Gaucher disease allele.
4
BP2 (Supporting): E326K occurs in cis with pathogenic L444P/N188S and is never found alone on a disease-causing allele.
5
BP5 (Supporting): affected family members carrying E326K have a documented alternate molecular basis (trans G202R or L444P).
6
Overall Benign: two strong benign criteria (BS2 + BS4) satisfy the Benign combination rule, with additional supporting BS1, BP2, and BP5.
Final determination: Generic ACMG/AMP 2015 fallback combination rule (PMID:25741868): two strong benign criteria (BS2 strong, BS4 strong) are met, and the rule '(2 BS) -> Benign' yields Benign; the additional supporting benign criteria (BS1, BP2, BP5) are consistent, and no pathogenic criterion is met, so no conflicting-evidence override applies.
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: this is a missense substitution, so none of the null-variant mechanisms PVS1 requires (nonsense-mediated decay, truncation, canonical splice disruption) are triggered.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Not met Not met: p.Glu365Lys (E326K) is documented as a non-pathogenic polymorphic allele, so no established-pathogenic same-amino-acid comparator exists.
PMID:12791040 PMID:15146461 PMID:16293621 PMID:25741868
PS2 Not met Not met: no de novo occurrence is documented; gnomAD v4.1 shows a 1.23% allele frequency with 196 homozygotes, and family data show paternal inheritance.
PMID:12791040 clinvar gnomad_v4 gnomad_v2
PS3 Not met Not met: functional studies show 43-55% residual glucocerebrosidase activity, far above the near-complete loss (<15%) seen in pathogenic GBA1 alleles.
PMID:15146461 PMID:16293621 PMID:26117366 PMID:12791040
PS4 Not met Not met: E326K showed no significant case-control enrichment (13/517 cases vs 3/252 controls, P=0.289). Flagged for human review: larger published E326K/PD association studies were not available for evaluation.
PMID:26117366 PMID:12791040
PM1 Not met Not met: Glu365 is a surface residue outside the active site, and the site carries abundant benign variation (gnomAD v4.1 AF 1.23%), failing the 'without benign variation' condition.
PMID:16293621 PMID:12791040 gnomad_v4 PMID:25741868
PM2 Not met Not met: gnomAD v4.1 allele frequency 1.23% is orders of magnitude above the <0.1% extremely-low-frequency threshold.
gnomad_v4 gnomad_v2 gnomad_canada PMID:25741868
PM3 Not met Not met: carriers with this allele in trans with pathogenic G202R or L444P are phenotypically normal, refuting a recessive pathogenic role.
PMID:12791040 PMID:15146461 PMID:26117366 gnomad_v2 gnomad_v4
PM4 N/A Not applicable: this is a missense substitution, so no protein-length change occurs for this criterion to evaluate.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Not met Not met: no different missense change at residue Glu365 has been established as pathogenic; the only characterized change there, p.Glu365Lys, is a common polymorphism.
pm5_candidates PMID:12791040 PMID:15146461 PMID:25741868
PM6 Not met Not met: no assumed de novo occurrence is documented, and a 1.23%-frequency polymorphism with 196 homozygotes is implausible as a de novo event.
PMID:12791040 clinvar gnomad_v4 gnomad_v2
PP1 Not met Not met: segregation data affirmatively contradict co-segregation - the affected proband lacks E326K while unaffected relatives carry it.
PMID:12791040 clinvar
PP2 Not met Not met: GBA1 has a high rate of benign missense variation - p.Glu365Lys itself is a 1.23%-frequency polymorphism (196 gnomAD v4.1 homozygotes).
PMID:12791040 PMID:15146461 PMID:16293621 gnomad_v4 PMID:25741868
PP3 Not met Not met: SpliceAI max delta 0.00 predicts no splice impact, and REVEL 0.595 falls below the 0.773 supporting threshold, so no calibrated computational support exists.
spliceai revel bayesdel clinvar cspec PMID:25741868
PP4 Not met Not met: the phenotype is not highly specific to a single genetic etiology - this allele is a low-penetrance Parkinson's risk factor, not a Gaucher disease-causing variant.
PMID:12791040 PMID:15146461 PMID:26117366 gnomad_v2
PP5 Not met Not met: ClinVar record VCV000199044 has zero expert-panel submissions, and only laboratory assertions exist, which cannot trigger PP5.
clinvar
BA1 Not met Not met: gnomAD v4.1 allele frequency 1.23% is below the >5% stand-alone benign threshold, and the allele is a documented low-penetrance Parkinson's risk factor.
gnomad_v4 gnomad_v2 PMID:25741868 PMID:26117366 PMID:15146461 cspec
BS1 Met Met (supporting): gnomAD v4.1 allele frequency 1.23% is 2.5-4x above the >0.3% convention and far exceeds the expected frequency for a Gaucher disease allele.
gnomad_v4 gnomad_v2 gnomad_canada PMID:25741868 PMID:12791040 PMID:26117366 cspec
BS2 Met Met (strong): 196 homozygotes in gnomAD v4.1 (and 37 in v2.1) are biallelic without Gaucher disease, indicating this allele does not cause the recessive disorder.
gnomad_v4 gnomad_v2 gnomad_canada PMID:12791040 PMID:16293621 PMID:15146461 PMID:25741868 cspec
BS3 Not met Not met: the ~40-55% residual enzyme activity is a partial functional deficit, so the studies do not establish that E326K has no damaging effect. Flagged for human review: the partial loss is mechanistically relevant to Parkinson's risk even though it argues against Gaucher pathogenicity.
PMID:15146461 PMID:16293621 PMID:26117366 PMID:12791040
BS4 Met Met (strong): in a Gaucher disease family, affected members lack E326K while unaffected relatives carry it (G202R/E326K, L444P/E326K), demonstrating lack of segregation with disease.
PMID:12791040 clinvar
BP1 N/A Not applicable: Gaucher disease and GBA1-related parkinsonism are caused predominantly by missense variants, so the truncating-variant premise of BP1 does not hold.
PMID:15146461 PMID:16293621 PMID:25741868
BP2 Met Met (supporting): E326K is observed in cis with pathogenic L444P or N188S on complex Gaucher alleles, and never alone on a disease-causing allele.
PMID:15146461 PMID:12791040
BP3 N/A Not applicable: this is a missense substitution, not an in-frame indel in a repetitive region, so BP3 does not apply.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Not met Not met: only one calibrated computational line exists (SpliceAI max delta 0.00); REVEL 0.595 is uninformative and in silico predictions disagree, failing the multiple-lines requirement.
spliceai revel bayesdel clinvar cspec PMID:25741868
BP5 Met Met (supporting): affected family members carry E326K alongside a documented alternate molecular basis - pathogenic G202R or L444P in trans.
PMID:12791040
BP6 Not met Not met: no ClinVar expert-panel benign classification exists for VCV000199044; only single-submitter laboratory assertions are present.
clinvar
BP7 N/A Not applicable: this is a missense substitution, not a synonymous variant, so the BP7 silent-variant premise does not hold.
generic_acmg_combination_rules
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