Variant classification summary

NM_000157.4:c.1226A>G

GBA1 · NP_000148.2:p.(Asn409Ser) · NM_000157.4

GRCh37: chr1:155205634 T>C · GRCh38: chr1:155235843 T>C

Gene: GBA1 Transcript: NM_000157.4

Final call

Pathogenic

PS3 strong PS4 strong PM1 moderate PP3 supporting PP4 supporting

Variant details

Gene

GBA1

Transcript

NM_000157.4

Protein

NP_000148.2:p.(Asn409Ser)

gnomAD AF

0.0019970085147040053 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000157.4:c.1226A>G (p.Asn409Ser; N370S) in GBA1 is a well-established pathogenic missense variant causing Gaucher disease type 1.

2

Multiple independent functional studies demonstrate consistently reduced glucocerebrosidase enzymatic activity for the N370S variant, satisfying PS3 at strong strength.

3

This variant is classified as Pathogenic in ClinVar by 45 clinical laboratories and is the most common Gaucher disease-associated mutation worldwide, satisfying PS4 at strong strength.

4

The N370 residue lies at the interface of the catalytic TIM barrel domain (domain III) and the immunoglobulin-like domain (domain II) of glucocerebrosidase, a critical functional region; disruption by N370S satisfies PM1 at moderate strength.

5

The REVEL in silico score of 0.673 supports a deleterious effect (PP3, supporting). The variant is associated with the highly specific phenotype of Gaucher disease type 1 (PP4, supporting).

6

The overall gnomAD allele frequency of 0.223% exceeds the PM2 threshold; PM2 is not met. The frequency is below both the BA1 (>1%) and BS1 (>0.3%) benign thresholds.

7

Applying the ACMG/AMP 2015 combination rules: PS3 (strong) + PS4 (strong) + PM1 (moderate) + PP3 (supporting) + PP4 (supporting) meets the threshold for Pathogenic classification.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Pathogenic classification based on the observed combination of very strong, strong, moderate, and supporting 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.1226A>G (p.Asn409Ser) is a missense variant and does not fall into the PVS1 null-variant buckets (nonsense, frameshift, or canonical splice consensus).	pvs1_generic_framework
PS1	N/A	No alternative nucleotide change resulting in the same amino acid substitution (p.Asn409Ser) has been reported; PS1 is not applicable.
PS2	Not assessed	No de novo data were reviewed for this case; GBA1-associated Gaucher disease is autosomal recessive, and PS2 (de novo) is rarely applicable.
PS3	Met	The N370S (p.Asn409Ser) variant has been directly tested in multiple independent functional studies demonstrating consistently reduced glucocerebrosidase enzymatic activity. Alfonso et al. (PMID:14757438) showed 32.1% residual activity in COS cells. Montfort et al. (PMID:15146461) showed 7.5% residual activity (11.6% CRIM-corrected) in Sf9 cells. Liou et al. (PMID:16293621) systematically characterized N370S with 12-15% CRIM SA and demonstrated defects in phospholipid activation. Offman et al. (PMID:20980259) used molecular dynamics to demonstrate the structural basis for reduced N370S catalytic activity. Two or more independent publications with variant-specific functional data qualify PS3 at strong strength.	PMID:14757438 PMID:15146461 PMID:16293621 PMID:20980259
PS4	Met	This variant has been reported in ClinVar as Pathogenic by 45 clinical laboratories and as Likely pathogenic by 4 clinical laboratories. It is the single most common Gaucher disease-associated variant worldwide, with extensive clinical observation in affected individuals. The variant is exclusively associated with type 1 (non-neuronopathic) Gaucher disease. A large international multicenter study (PMID:19846850) confirmed significant enrichment in Parkinson disease patients (OR 3.96, 95% CI 2.6-6.02).	clinvar PMID:19846850
PS5	N/A	GBA1-associated Gaucher disease is autosomal recessive; PS5 is not applicable in a recessive disease model.
PM1	Met	The N370 (p.Asn409) residue is located at the interface of domains II and III of glucocerebrosidase (the TIM barrel domain), a well-characterized critical functional region. Functional studies demonstrate that N370S disrupts saposin C interaction and anionic phospholipid-mediated enzyme activation (PMID:15146461, PMID:16293621, PMID:20980259). The variant lies within a critical functional domain of the enzyme.	PMID:15146461 PMID:16293621 PMID:20980259
PM2	Not met	The variant is present in gnomAD v2.1 at an overall allele frequency of 0.223% (632/282,786 alleles) and in gnomAD v4.1 at 0.200% (3223/1,613,914 alleles). Both exceed the PM2 threshold of <0.1%. The grpmax filtering allele frequency is 0.186% (gnomAD v2.1), also above the threshold. PM2 is not met.	gnomad_v2 gnomad_v4
PM5	Not assessed	No confirmed same-residue comparator variants (classic PM5 semantics) were identified. The pm5_candidates.json report found no eligible candidates for this variant. The N370 position has other pathogenic variants reported in ClinVar (e.g. N370K), but these were not systematically harvested in the case materials.
PM6	N/A	GBA1-associated Gaucher disease is autosomal recessive. PM6 (de novo) is not applicable in a recessive disorder without specific de novo evidence.
PP1	Not assessed	No co-segregation data were reviewed in the case materials. Co-segregation analysis was not performed for this case.
PP2	Not met	GBA1 has a well-established spectrum of pathogenic missense variants, but it also harbors known benign or low-penetrance missense variants (e.g., E326K, T369M). The gene does not meet the strict PP2 requirement of a low rate of benign missense variation. Constraint metrics were not available in the case materials to support PP2.	PMID:19846850
PP3	Met	REVEL score of 0.673 (>0.5 threshold) supports a deleterious effect. BayesDel score of 0.0416 is low but does not independently contradict. SpliceAI max delta = 0.00 indicates no predicted splicing impact. A single in silico predictor (REVEL) supports pathogenicity at the supporting level.	revel bayesdel spliceai
PP4	Met	Gaucher disease is a highly specific clinical phenotype. The N370S variant is the most common cause of type 1 Gaucher disease and is exclusively associated with the non-neuronopathic form. The phenotype is well-characterized and highly specific for GBA1 deficiency.	clinvar PMID:14757438 PMID:15146461
PP5	N/A	PS4 has been applied based on ClinVar observational data. PP5 is redundant with PS4 and should not be double-counted.
BA1	Not met	Overall gnomAD v2.1 allele frequency of 0.223% is below the BA1 threshold of >1%. The highest subpopulation frequency (Ashkenazi Jewish) is 2.69%, but BA1 uses the overall or grpmax frequency. The grpmax FAF is 0.186%, well below 1%. BA1 is not met.	gnomad_v2 gnomad_v4
BS1	Not met	Overall gnomAD v2.1 allele frequency of 0.223% is below the BS1 threshold of >0.3%. The grpmax FAF of 0.186% also falls below the threshold. BS1 is not met.	gnomad_v2 gnomad_v4
BS2	Not met	While homozygous individuals are observed in gnomAD (4 in v2.1, 8 in v4.1), Gaucher disease type 1 is an adult-onset, often mild disorder compatible with survival into population databases. Observation in gnomAD does not constitute healthy adult controls for this phenotype, as N370S homozygotes are known to have Gaucher disease. BS2 cannot be applied without confirmed healthy adult homozygous status.	gnomad_v2 gnomad_v4
BS3	Not met	All functional studies demonstrate reduced glucocerebrosidase enzymatic activity for N370S. No study shows normal or near-normal activity. The variant is functionally damaging, not benign. BS3 requires in vitro studies showing no damaging effect, which is contradicted by the available evidence.	PMID:14757438 PMID:15146461 PMID:16293621
BS4	Not assessed	No segregation data were reviewed in the case materials. BS4 requires lack of segregation in affected family members, which cannot be assessed without such data.
BP1	Not met	GBA1 has many well-established pathogenic missense variants (including N370S itself, L444P, D409H, and others). Missense variants are a primary disease mechanism; GBA1 is not a gene where primarily truncating variants cause disease. BP1 is not applicable.	PMID:14757438 PMID:15146461
BP2	N/A	BP2 applies to variants observed in trans with a pathogenic variant in a recessive disorder when the phenotype is inconsistent. This variant IS the pathogenic variant; BP2 is not applicable.
BP4	Not met	REVEL score of 0.673 (>0.5) supports a deleterious effect. BayesDel score of 0.0416 does not independently support a benign interpretation. Multiple computational predictors do not agree on a benign effect; BP4 requires multiple lines of computational evidence suggesting no impact. Not met.	revel bayesdel spliceai
BP5	N/A	BP5 applies to variants found in a case with an alternate molecular basis for disease. Not applicable in this context.
BP6	N/A	BP6 (reputable source reports variant as benign) is not applicable; ClinVar classifies this variant as Pathogenic, not benign.
BP7	Not met	NM_000157.4:c.1226A>G is a missense variant (p.Asn409Ser), not a synonymous or intronic variant. BP7 applies only to synonymous variants at non-conserved nucleotides. Not met.
BP3	N/A	Skipped — trivially not applicable (in-frame indels only).
PM3	N/A	Skipped — trivially not applicable per case instructions.
PM4	N/A	Skipped — trivially not applicable (non-frameshift indel only).

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