About GBA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
GBA1 c.1226A>G, p.(Asn409Ser)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen GBA1 VCEP v1.0.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 5
Benign evidence criteria: 0
Pathogenic criteria applied · 5
PS3Strong
PS3 · strong
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.
PS4Strong
PS4 · strong
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).
PM1Moderate
PM1 · moderate
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.
PP3Supporting
PP3 · supporting
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.
PP4Supporting
PP4 · supporting
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
ClinGen Parkinson's Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GBA1 Version 1.0.0 v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 strong, PS4 strong, PM1 moderate, PP3 supporting, PP4 supporting; combination = 2 strong + 1 moderate + 2 supporting, which maps to Pathogenic.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
3,223 / 1,613,914 alleles
gnomAD v4.1: 3,223 / 1,613,914 alleles. Recorded AF 0.00199701. Recorded homozygote count 8.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00223491; MAF= 0.22349%, 632/282786 alleles, homozygotes = 4) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0269097; MAF= 2.69097%, 279/10368 alleles, homozygotes = 2); grpmax FAF= 0.00185794.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0028773072747014113, 53/18420 alleles, homozygotes = 0).
No listed criterion applied
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
50 reported laboratory submissions
45 Pathogenic · 4 Likely pathogenic · 1 risk factor. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen GBA1 VCEP v1.0.0, with the data and sources behind each one.
29 criteria with recorded statuses: 5 met · 9 not met · 4 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000157.4:c.1226A>G (p.Asn409Ser; N370S) in GBA1 is a well-established pathogenic missense variant causing Gaucher disease type 1.
Multiple independent functional studies demonstrate consistently reduced glucocerebrosidase enzymatic activity for the N370S variant, satisfying PS3 at strong strength.
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.
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.
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).
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.
Applying the ACMG/AMP 2015 combination rules: PS3 (strong) + PS4 (strong) + PM1 (moderate) + PP3 (supporting) + PP4 (supporting) meets the threshold for Pathogenic classification.
No criteria match.
Met · 5
PS3 StrongThe 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. Details ▾Hide ▴
Evidence considered
- PMID:14757438: N370S expressed in COS-7 cells
- 32.1% residual GCase activity versus wild-type.
- PMID:15146461: N370S expressed in Sf9 cells via baculovirus
- 7.5% residual activity (11.6% CRIM-corrected).
- PMID:16293621: Systematic characterization of 52 GCase variants including N370S
- CRIM SA ~12-15%
- defects in phospholipid activation confirmed.
- PMID:20980259: Molecular dynamics simulations of N370S demonstrating altered active-site hydrogen bonding and reduced catalytic activity at lysosomal pH.
Sources
PS4 StrongThis 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). Details ▾Hide ▴
Evidence considered
- ClinVar Variation ID 4290: Pathogenic
- 45 clinical laboratories
- Likely pathogenic
- 4 clinical laboratories.
- PMID:19846850: Combined OR for N370S in Parkinson disease = 3.96 (95% CI 2.6-6.02) across 16 centers
- 5691 cases and 4898 controls.
Sources
PM1 ModerateThe 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. Details ▾Hide ▴
Evidence considered
- N370 is located at the interface of the TIM barrel catalytic domain (domain III) and the immunoglobulin-like domain (domain II).
- PMID:16293621: N370S shows deficits in saposin C enhancement of kcat and altered phospholipid activation.
- PMID:20980259: N370S alters active site hydrogen bonding network
- affecting catalytic function.
Sources
PP3 SupportingREVEL 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.673 (>0.5
- supports deleterious).
- BayesDel: 0.0416 (low
- does not independently support pathogenicity).
- SpliceAI max delta: 0.00 (no predicted splice impact).
Sources
PP4 SupportingGaucher 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. Details ▾Hide ▴
Evidence considered
- N370S is exclusively associated with type 1 (non-neuronopathic) Gaucher disease.
- The variant is neuroprotective: presence of one N370S allele prevents neuronopathic disease.
Sources
Not met · 9 · evaluated, threshold not reached
PM2 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF = 0.223%
- 632/282786 alleles
- 4 homozygotes
- grpmax FAF = 0.186%.
- gnomAD v4.1: AF = 0.200%
- 3223/1613914 alleles
- 8 homozygotes
- grpmax FAF = 0.166%.
Sources
PP2 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. Details ▾Hide ▴
Evidence considered
- PMID:19846850: E326K and T369M were evaluated as common GBA variants not associated with disease
- indicating benign missense variation exists in GBA1.
Sources
BA1 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF = 0.223%
- grpmax FAF = 0.186%.
- gnomAD v4.1: AF = 0.200%
- grpmax FAF = 0.166%.
Sources
BS1 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. Details ▾Hide ▴
BS2 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 4 homozygotes.
- gnomAD v4.1: 8 homozygotes.
- N370S homozygotes have Gaucher disease type 1
- these individuals are not confirmed healthy controls.
Sources
BS3 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. Details ▾Hide ▴
Evidence considered
- PMID:14757438: 32.1% residual activity — reduced.
- PMID:15146461: 7.5-11.6% residual activity — reduced.
- PMID:16293621: 12-15% CRIM SA — reduced.
Sources
BP1 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. Details ▾Hide ▴
Evidence considered
- Numerous pathogenic missense variants in GBA1 are well-characterized
- missense changes are a primary mechanism of disease.
Sources
BP4 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.673 (supports deleterious
- not benign).
- BayesDel: 0.0416 (low
- but does not robustly support benign).
- SpliceAI: 0.00 (no splice impact — neutral).
Sources
BP7 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. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous.
Not assessed · 4 · no assessment recorded
PS2 No de novo data were reviewed for this case; GBA1-associated Gaucher disease is autosomal recessive, and PS2 (de novo) is rarely applicable. Details ▾Hide ▴
Still missing
- No de novo data in case materials.
PM5 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. Details ▾Hide ▴
Evidence considered
- pm5_candidates.json: 0 candidates identified
- same-residue semantics not confirmed by automated harvesting.
Still missing
- Manual review of same-residue comparator variants at N370 (e.g.
- N370K in ClinVar) may identify PM5 candidates.
PP1 No co-segregation data were reviewed in the case materials. Co-segregation analysis was not performed for this case. Details ▾Hide ▴
Still missing
- No segregation data in case materials.
BS4 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. Details ▾Hide ▴
Still missing
- No segregation data in case materials.
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_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). Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not a null variant eligible for PVS1 per ClinGen SVI PVS1 recommendations (PMC6185798).
Sources
PS1 N/ANo alternative nucleotide change resulting in the same amino acid substitution (p.Asn409Ser) has been reported; PS1 is not applicable. Details ▾Hide ▴
No further detail was recorded.
PM3 N/ASkipped — trivially not applicable per case instructions. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ASkipped — trivially not applicable (non-frameshift indel only). Details ▾Hide ▴
No further detail was recorded.
PM6 N/AGBA1-associated Gaucher disease is autosomal recessive. PM6 (de novo) is not applicable in a recessive disorder without specific de novo evidence. Details ▾Hide ▴
No further detail was recorded.
PP5 N/APS4 has been applied based on ClinVar observational data. PP5 is redundant with PS4 and should not be double-counted. Details ▾Hide ▴
No further detail was recorded.
BP2 N/ABP2 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. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ASkipped — trivially not applicable (in-frame indels only). Details ▾Hide ▴
No further detail was recorded.
BP5 N/ABP5 applies to variants found in a case with an alternate molecular basis for disease. Not applicable in this context. Details ▾Hide ▴
No further detail was recorded.
BP6 N/ABP6 (reputable source reports variant as benign) is not applicable; ClinVar classifies this variant as Pathogenic, not benign. Details ▾Hide ▴
Evidence considered
- ClinVar: Pathogenic
- not benign.
PS5 N/AGBA1-associated Gaucher disease is autosomal recessive; PS5 is not applicable in a recessive disease model. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- GBA1
- Transcript
- NM_000157.4
- Coding (HGVS c.)
- NM_000157.4:c.1226A>G
- Protein (HGVS p.)
- NP_000148.2:p.(Asn409Ser)
- GRCh38
- chr1:155235843 T>C
- GRCh37
- chr1:155205634 T>C
- ClinVar
- 3769395, 4290, 633239, 65570
Gene diagram
Every interpreted variant in GBA1, mapped onto the exon structure of NM_000157.4. Select a row to find it on the plot.
GBA1NM_000157.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in GBA1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
3,223 / 1,613,914 alleles
AF 0.002 · 8 homozygotes · FAF 0.00166
gnomAD v2.1
632 / 282,786 alleles
AF 0.00223 · 4 homozygotes · FAF 0.00186
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.002 · 3223 / 1,613,914 alleles · 8 hom · FAF 0.0017
| Ashkenazi Jewish839 / 29,602 | 0.0285 hom |
| Amish16 / 908 | 0.0181 hom |
| Remaining individuals188 / 62,502 | 0.003 |
| European (non-Finnish)2039 / 1,179,960 | 0.00172 hom |
| Admixed American57 / 60,010 | 0.00095 |
| European (Finnish)58 / 63,994 | 0.00091 |
| Middle Eastern5 / 6,062 | 0.00082 |
| African/African American16 / 74,932 | 0.00021 |
| South Asian5 / 91,072 | 5.5e-05 |
0 alternate alleles recorded in 1 other group: East Asian.
gnomAD v2.1
AF 0.0022 · 632 / 282,786 alleles · 4 hom · FAF 0.0019
| Ashkenazi Jewish279 / 10,368 | 0.0272 hom |
| Remaining individuals23 / 7,226 | 0.0032 |
| European (non-Finnish)264 / 129,124 | 0.0022 hom |
| European (Finnish)33 / 25,116 | 0.0013 |
| Admixed American27 / 35,432 | 0.00076 |
| African/African American5 / 24,952 | 0.0002 |
| South Asian1 / 30,616 | 3.3e-05 |
0 alternate alleles recorded in 1 other group: East Asian.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.00199701; MAF= 0.19970%, 3223/1613914 alleles, homozygotes = 8) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0283427; MAF= 2.83427%, 839/29602 alleles, homozygotes = 5); grpmax FAF= 0.00166478.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00223491; MAF= 0.22349%, 632/282786 alleles, homozygotes = 4) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0269097; MAF= 2.69097%, 279/10368 alleles, homozygotes = 2); grpmax FAF= 0.00185794.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0028773072747014113, 53/18420 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.673
- BayesDel
- 0.042
How the predictions were used
PP3 SupportingREVEL 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.673 (>0.5
- supports deleterious).
- BayesDel: 0.0416 (low
- does not independently support pathogenicity).
- SpliceAI max delta: 0.00 (no predicted splice impact).
Sources
BP4 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.673 (supports deleterious
- not benign).
- BayesDel: 0.0416 (low
- but does not robustly support benign).
- SpliceAI: 0.00 (no splice impact — neutral).
Sources
BP7 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. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.673. BayesDel score = 0.0416346.
9 paper records listed. 7 cited in the classification.
Cited in the classification
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PMID 10079102 ↗Non-pseudogene-derived complex acid beta-glucosidase mutations causing mild type 1 and severe type 2 gaucher disease.Grace ME et al. · 1999 MarDescribes N370S as the most common Gaucher disease mutation, with heteroallelism or homoallelism for N370S found in approximately 50% of Ashkenazi Jewish patients with type 1 disease. Reports that the N370S allele encodes a protein with significant CRIM SA and is neuroprotective, precluding neurologic manifestations. Expresses and characterizes N370S alongside other mutants in the baculovirus system, confirming N370S has ~20-24% of normal CRIM SA.→ PS3 → PM1 → PP4 Names this variant
Source detail
the presence of one N370S allele, which encodes a protein with significant CRIM SA, is neuroprotective, precluding the development of neurologic manifestations and resulting in the type 1 phenotype
Location Introduction, Results, Table 3, Discussion
Context Baculovirus expression in Sf9 cells; CRIM SA quantified from immunoblots
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PMID 14757438 ↗Expression and functional characterization of mutated glucocerebrosidase alleles causing Gaucher disease in Spanish patients.Alfonso P et al. · 2004 Jan-FebExpressed c.1226A>G (N370S) in COS-7 cells along with six novel GBA mutations. N370S showed 32.1% residual glucocerebrosidase activity using the synthetic 4MU-Glu substrate, used as a 'mild' mutation reference. Confirmed N370S is exclusively associated with type 1 Gaucher disease.→ PS3 → PP4 Names this variant
Source detail
the N370S mutation has been associated exclusively with type 1 GD
Location Abstract, Introduction, Results (Fig. 1), Discussion
Context Transient transfection in COS-7 cells; activity measured with 4-methylumbelliferyl-beta-D-glucopyranoside (4MU-Glu)
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PMID 15146461 ↗Functional analysis of 13 GBA mutant alleles identified in Gaucher disease patients: Pathogenic changes and "modifier" polymorphisms.Montfort M et al. · 2004 JunExpressed c.1226A>G (N370S) in Sf9 cells using baculovirus expression alongside 12 other GBA mutant alleles. N370S showed 7.5% residual glucocerebrosidase activity (11.6% after CRIM correction), consistent with previously reported in vitro results for this mild mutation. The N370S enzyme showed reduced CRIM amounts on immunoblot. Comparative analysis across multiple expression systems is provided in Table 4.→ PS3 → PM1 → PP4 Names this variant
Source detail
One surprising but repetitive result is that mutation c.1226A4G (p.N370S), always associated with a mild phenotype, shows low levels of activity when expressed in vitro
Location Abstract, Results (Fig. 2, Table 3, Table 4), Discussion
Context Baculovirus expression in Sf9 insect cells; activity measured with 4MU-Glu; CRIM correction via Western blot with polyclonal antibody
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PMID 16293621 ↗Analyses of variant acid beta-glucosidases: effects of Gaucher disease mutations.Systematically characterized 52 GCase single amino acid substitutions including N370S expressed in Sf21 cells via baculovirus. N370S showed CRIM SA of 12-15% of wild-type, with a defect in negatively charged phospholipid activation. N370S was classified among variants with moderate CRIM SA (approximately 10%). The N370 residue is at the interface of domains II and III, flanking the active site. Saposin C enhancement of kcat was preserved but phospholipid activation was altered.→ PS3 → PM1 Names this variant
Source detail
A defect in negatively charged phospholipid activation was present in the majority of variant GCases but was increased in two, N370S and V394L
Location Abstract, Results, Table 1, Discussion, Figs. 1-6
Context Baculovirus expression in Sf21 cells; purified GCases; 4MUG substrate; phospholipid activation and saposin C enhancement assays; cathepsin D sensitivity assays
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PMID 19846850 ↗Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease.International multicenter collaborative study screening 5691 Parkinson disease cases and 4898 controls for GBA mutations. N370S was one of two primary mutations screened. Combined OR for N370S across centers was 3.96 (95% CI 2.6-6.02) for Parkinson disease risk. N370S was particularly prevalent among Ashkenazi Jews (OR 5.62, 95% CI 3.04-10.39) and absent among Asians. Fourteen N370S homozygotes were identified among patients (genotype N370S/N370S).→ PS4 Names this variant
Source detail
Combined ORs for Mantel-Haenszel analyses were homogenous for L444P and N370S... Combined ORs attributable to N370S (OR = 3.96, 95% CI 2.6-6.02)
Location Abstract, Introduction, Results, Figure 1, Supplementary material
Context Multicenter case-control genotyping; various screening methods including full sequencing
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PMID 20980259 ↗Molecular basis of reduced glucosylceramidase activity in the most common Gaucher disease mutant, N370S.Molecular dynamics simulations of wild-type and N370S glucocerebrosidase at various pH values with and without chaperone (NB-DNJ). N370S is more stable than WT at pH 7.4 but has altered active site hydrogen bonding at pH 4.5, explaining the reduced catalytic activity. NB-DNJ binding stabilizes the N370S-saposin C interaction interface. The structural basis for the shifted pH optimum (5.5-6.4 vs. 4.5 for WT) is demonstrated.→ PS3 → PM1 Names this variant
Source detail
the most dramatic and statistically significant changes between WT and N370S in HBs were observed for the amino acid pairs 312-370, 313-340, 313-342, and 315-366, which are likely to affect the integrity of the active site, causing the reduced catalytic activity of GCase(N370S)-pH 4.5
Location Abstract, Results (RMSF Analysis, Active Site Volume, HB Network), Discussion
Context Molecular dynamics simulations using AMBER10; 25 independent MD runs; active site volume, hydrogen bonding, RMSF, and solvent-accessible surface analyses
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PMID 21472771 ↗Acid β-glucosidase mutants linked to Gaucher disease, Parkinson disease, and Lewy body dementia alter α-synuclein processing.Investigated the effect of GBA mutants (N370S, L444P, D409H, D409V, E235A, E340A) on alpha-synuclein processing. N370S overexpression in neural MES23.5 and PC12 cells significantly raised human SNCA levels (124% of vector control, p<0.05) without altering GCase activity. This provides a biochemical link between GBA1 mutation carrier status and increased synucleinopathy risk. N370S shows a gain-of-function effect on SNCA accumulation independent of GCase activity loss.→ PS3 Names this variant
Source detail
overexpression of all GBA mutants examined (N370S, L444P, D409H, D409V, E235A, and E340A) significantly raised human SNCA levels to 121 to 248% of vector control (p < 0.029)
Location Abstract, Results, Table
Context Neural MES23.5-SNCA, PC12-SNCA, and HEK293-SNCA cell lines; transient cDNA overexpression; ELISA for SNCA quantification
Other recorded publications
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PMID 1864608 ↗Three unique base pair changes in a family with Gaucher disease.Reports three novel base-pair changes (D140H, K157Q, E326K) in a family with Gaucher disease type 1. The c.1226A>G (N370S) variant was not identified or discussed in this paper.Does not name this variant
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PMID 23676350 ↗Mutations in GBA and risk of Parkinson's disease: a meta-analysis based on 25 case-control studies.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
3,223 / 1,613,914 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
45 Pathogenic · 4 Likely pathogenic · 1 risk factor
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1833089217
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/4290/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-155205634-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-155235843-T-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/1-155235843-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000157.4%3Ac.1226…
- OncoKB ↗www.oncokb.org/gene/GBA1/N409S
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=GBA1+c.1226A%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.00199701; MAF= 0.19970%, 3223/1613914 alleles, homozygotes = 8) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0283427; MAF= 2.83427%, 839/29602 alleles, homozygotes = 5); grpmax FAF= 0.00166478.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00223491; MAF= 0.22349%, 632/282786 alleles, homozygotes = 4) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0269097; MAF= 2.69097%, 279/10368 alleles, homozygotes = 2); grpmax FAF= 0.00185794.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0028773072747014113, 53/18420 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Pathogenic (45 clinical laboratories) and as Likely pathogenic (4 clinical laboratories) and as risk factor (1 clinical laboratory). (ClinVarID = 4290)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.673. BayesDel score = 0.0416346.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.