NM_000157.4:c.1279G>A (p.Glu427Lys) is a missense variant in exon 9 of GBA1, located within the catalytic domain of glucocerebrosidase.1 This variant is present at very low frequency in population databases: gnomAD v2.1 AF=0.0159% (45/282,860 alleles) and gnomAD v4.1 AF=0.0193% (311/1,614,180 alleles), with no homozygotes observed (PM2_Supporting).2 The variant is located within the well-characterized catalytic domain of GBA1 where multiple pathogenic missense variants cluster (PM1_Supporting).3 This variant has been reported in ClinVar as Uncertain significance by 7 clinical laboratories (ClinVar Variation ID: 493050), with no expert panel classification available.4 In silico predictors are mixed: REVEL score is 0.579 (intermediate), BayesDel is 0.107 (benign-leaning), and SpliceAI predicts no splicing impact (max delta 0.07). Multiple lines of computational evidence do not consistently support a pathogenic or benign interpretation (PP3 not met, BP4 not met).5 Exploratory literature review identified potential functional evidence (PMID:10079102, PMID:15300782) reporting severely reduced glucocerebrosidase activity for E427K, and potential co-segregation evidence (PMID:9375849). However, full-text verification was not available in this case to confirm exact variant-specific data (PS3 and PP1 not assessed pending full-text review). Applying generic ACMG/AMP 2015 combination rules: PM1_Supporting + PM2_Supporting = 2 supporting pathogenic criteria. No benign criteria are met. This is consistent with a final classification of Variant of Uncertain Significance (VUS).6
GBA1
Final classification
VUS
GBA1 c.1279G>A · p.Glu427Lys
GBA1
NM_000157.4:c.1279G>A (p.Glu427Lys) is a missense variant in exon 9 of GBA1, located within the catalytic domain of glucocerebrosidase.
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: PM1 supporting, PM2 supporting; combination = 2 supporting, which maps to VUS.
Classification rationale
PM1PM2
VUS
GBA1 c.1279G>A
PM1 + PM2
→
VUS
Gene diagram
· NM_000157.4 · variants mapped to exon structure
GBA1
NM_000157.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM1
supporting
review
Pathogenic
Residue Glu427 is located within the well-characterized catalytic domain of glucocerebrosidase (GBA1). The GBA1 ClinGen Parkinson's Disease VCEP v1.0.0 does not provide explicit domain-level specifications; however, under generic ACMG/AMP rules, location in a critical functional domain where multiple pathogenic missense variants cluster supports PM1 at a supporting level.
Glu427 is within the GBA1 catalytic domain (UniProt P04062)multiple pathogenic missense variants reported at nearby residuesexploratory search confirmed domain-level functional significance.
✓
PM2
supporting
Pathogenic
This variant is present at very low frequency in population databases: gnomAD v2.1 AF=0.0159% (45/282,860 alleles) and gnomAD v4.1 AF=0.0193% (311/1,614,180 alleles), both below the 0.1% threshold for PM2. No homozygotes observed. Absent from gnomAD-Canada v1.0.
gnomAD v2.1: AF=0.000159 (45/282860 alleles0 homozygotes)
Assessed · not applied
Pathogenic
PS1
No evidence was identified for a different nucleotide change at the same codon producing the same amino acid change (p.Glu427Lys) that has been previously classified as pathogenic.
PS2
No published de novo occurrence of GBA1 c.1279G>A with confirmed parentage was identified in ClinVar or the available literature.
PS3
Exploratory literature search identified two functional studies (PMID:10079102 Grace et al.
PS4
No case-control study directly comparing the prevalence of GBA1 c.1279G>A in affected individuals versus controls was identified.
PM5
PM5 candidate harvesting was unable to confirm classic same-residue PM5 semantics safely.
PM6
No published de novo occurrence of GBA1 c.1279G>A (with or without paternity confirmation) was identified in ClinVar or the available literature.
PP1
Exploratory literature search identified a report (PMID:9375849, Ida et al.
PP2
PP2 requires demonstration that the gene has a low rate of benign missense variation and that missense variants are a common disease mechanism.
PP3
Multiple lines of computational evidence do not consistently support a deleterious effect.
PP4
No detailed phenotype or family history information specific to the proband was provided in this case to assess whether the variant's phenotype is highly specific for the disease.
PP5
ClinVar reports this variant as Uncertain significance (7 clinical laboratories, review status: criteria provided, single submitter).
Benign
BA1
The variant allele frequency in gnomAD (v2.1: 0.0159%; v4.1: 0.0193%) is far below the BA1 threshold of >1% (non-VCEP) or >5% (generic ACMG/AMP).
BS1
The variant allele frequency in gnomAD (v2.1: 0.0159%; v4.1: 0.0193%) is below the non-VCEP BS1 threshold of >0.3%.
BS2
No homozygous observations of this variant are reported in gnomAD v2.1 or v4.1.
BS3
Published functional studies identified in the exploratory search (PMID:10079102, PMID:15300782) report a damaging effect (severely reduced enzyme activity) for E427K, not a benign effect.
BS4
No family studies demonstrating lack of segregation of c.1279G>A with disease phenotype were identified.
BP1
GBA1 missense variants are a well-established cause of both autosomal recessive Gaucher disease and Parkinson's disease risk.
BP2
GBA1 is associated with autosomal recessive Gaucher disease.
BP4
Multiple lines of computational evidence do not consistently suggest no impact.
BP5
No case was identified in which this variant is found in an individual with an alternate molecular basis for disease, while the individual's phenotype or family history is specific for the gene-associated condition.
BP6
ClinVar reports this variant as Uncertain significance (7 clinical laboratories).
N/A · 3
PVS1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000192667; MAF= 0.01927%, 311/1614180 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000222873; MAF= 0.02229%, 263/1180044 alleles, homozygotes = 0); grpmax FAF= 0.00020027.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.000159089; MAF= 0.01591%, 45/282860 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000263207; MAF= 0.02632%, 34/129176 alleles, homozygotes = 0); grpmax FAF= 0.00021135.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.00021720243266724586, 4/18416 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.019%
· 311 / 1,614,180
0 hom · FAF 0.02%
0 hom · FAF 0.02%
European (non-Finnish) 263 / 1,180,044 |
0.022% |
South Asian 20 / 91,084 |
0.022% |
Remaining individuals 13 / 62,506 |
0.021% |
Middle Eastern 1 / 6,062 |
0.016% |
European (Finnish) 9 / 64,038 |
0.014% |
Admixed American 4 / 60,024 |
0.0067% |
African/African American 1 / 75,016 |
0.0013% |
+ 3 not observed (Amish, East Asian, Ashkenazi Jewish)
gnomAD v2.1
0.016%
· 45 / 282,860
0 hom · FAF 0.021%
0 hom · FAF 0.021%
European (non-Finnish) 34 / 129,176 |
0.026% |
Remaining individuals 1 / 7,226 |
0.014% |
South Asian 4 / 30,616 |
0.013% |
European (Finnish) 3 / 25,120 |
0.012% |
Admixed American 2 / 35,432 |
0.0056% |
African/African American 1 / 24,966 |
0.004% |
+ 2 not observed (Ashkenazi Jewish, East Asian)
gnomAD Canada 🇨🇦
0.022%
· 4 / 18,416
0 hom
0 hom
Latino/Admixed American 1 / 836 |
0.12% |
Remaining individuals 1 / 1,138 |
0.088% |
European (non-Finnish) 2 / 11,738 |
0.017% |
+ 6 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, South Asian)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories). (ClinVarID = 493050)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.579. BayesDel score = 0.107037.
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 9 PMIDs not cited in assessment
22820396 ↗
First pilot newborn screening for four lysosomal storage diseases in an Italian region: identification and analysis of a putative causative mutation in the GBA gene.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
32658388 ↗
GBA-Related Parkinson's Disease: Dissection of Genotype-Phenotype Correlates in a Large Italian Cohort.
CLINVAR
23035075 ↗
GBA mutations increase risk for Lewy body disease with and without Alzheimer disease pathology.
CLINVAR
23588557 ↗
A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies.
CLINVAR
30302829 ↗
Coding variation in GBA explains the majority of the SYT11-GBA Parkinson's disease GWAS locus.
CLINVAR
32618053 ↗
A Large-Scale Full GBA1 Gene Screening in Parkinson's Disease in the Netherlands.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR