Variant classification summary

NM_000157.4:c.1279G>A

GBA1 · NP_000148.2:p.(Glu427Lys) · NM_000157.4

GRCh37: chr1:155205581 C>T · GRCh38: chr1:155235790 C>T

Gene: GBA1 Transcript: NM_000157.4

Final call

VUS

PM1 supporting PM2 supporting

Variant details

Gene

GBA1

Transcript

NM_000157.4

Protein

NP_000148.2:p.(Glu427Lys)

gnomAD AF

0.00019266748441933366 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000157.4:c.1279G>A (p.Glu427Lys) is a missense variant in exon 9 of GBA1, located within the catalytic domain of glucocerebrosidase.

2

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).

3

The variant is located within the well-characterized catalytic domain of GBA1 where multiple pathogenic missense variants cluster (PM1_Supporting).

4

This variant has been reported in ClinVar as Uncertain significance by 7 clinical laboratories (ClinVar Variation ID: 493050), with no expert panel classification available.

5

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).

6

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).

7

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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.1279G>A is a missense variant (p.Glu427Lys) and does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for PVS1 application per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	Not assessed	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	Not met	No published de novo occurrence of GBA1 c.1279G>A with confirmed parentage was identified in ClinVar or the available literature.	clinvar
PS3	Not assessed	Exploratory literature search identified two functional studies (PMID:10079102 Grace et al. 1999; PMID:15300782 Montfort et al. 2004) reporting E427K resulting in <10% wild-type glucocerebrosidase activity in heterologous expression systems. However, full-text verification was not available in this case to confirm the exact variant data, assay validation, and experimental details required to apply PS3.
PS4	Not assessed	No case-control study directly comparing the prevalence of GBA1 c.1279G>A in affected individuals versus controls was identified. Several cohort studies (PMID:25249066, PMID:32658388, PMID:32618053) screened GBA1 in Parkinson's disease cohorts, but full-text verification was not available to confirm whether c.1279G>A was observed and at what frequency.
PS5	Not assessed	No different missense change at residue 427 with an established pathogenic classification was identified for comparison. PM5 candidate harvesting found no same-residue comparator variants with confirmed pathogenic status.
PM1	Met	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.	cspec
PM2	Met	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 gnomad_v4 gnomad_canada
PM5	Not assessed	PM5 candidate harvesting was unable to confirm classic same-residue PM5 semantics safely. No same-residue comparator variants (different amino acid change at Glu427) with pathogenic classification were identified in ClinVar.
PM6	Not met	No published de novo occurrence of GBA1 c.1279G>A (with or without paternity confirmation) was identified in ClinVar or the available literature.	clinvar
PP1	Not assessed	Exploratory literature search identified a report (PMID:9375849, Ida et al. 1997) of a Japanese family with Gaucher disease where multiple affected siblings carried E427K co-segregating with the disease phenotype. However, full-text verification was not available in this case to confirm the number of meioses and segregation pattern.
PP2	Not assessed	PP2 requires demonstration that the gene has a low rate of benign missense variation and that missense variants are a common disease mechanism. GBA1 is known to have many pathogenic missense variants associated with both autosomal recessive Gaucher disease and Parkinson's disease risk. However, gene-level missense constraint metrics (e.g., missense Z-score, o/e ratio) were not provided in this case, and the GBA1 VCEP does not specify PP2 rules.
PP3	Not met	Multiple lines of computational evidence do not consistently support a deleterious effect. REVEL score is 0.579 (intermediate, below typical pathogenic threshold), BayesDel score is 0.107 (benign-leaning), and SpliceAI predicts no significant splicing impact (max delta = 0.07). HCI prior is not available for GBA1.	revel bayesdel spliceai
PP4	Not assessed	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	Not met	ClinVar reports this variant as Uncertain significance (7 clinical laboratories, review status: criteria provided, single submitter). No reputable source has reported the variant as pathogenic. The ACMG/AMP guideline paper (PMID:25741868) and Sherloc paper (PMID:28492532) are methodological references and do not classify this specific variant.	clinvar PMID:25741868 PMID:28492532
BA1	Not met	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).	gnomad_v2 gnomad_v4
BS1	Not met	The variant allele frequency in gnomAD (v2.1: 0.0159%; v4.1: 0.0193%) is below the non-VCEP BS1 threshold of >0.3%. The frequency is not greater than expected for Gaucher disease or Parkinson's disease risk.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous observations of this variant are reported in gnomAD v2.1 or v4.1. The variant has not been observed in a healthy adult in the homozygous state.	gnomad_v2 gnomad_v4
BS3	Not met	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. No well-established functional study indicates a benign effect for this variant.
BS4	Not assessed	No family studies demonstrating lack of segregation of c.1279G>A with disease phenotype were identified. The exploratory search found potential co-segregation evidence (PMID:9375849) supporting pathogenicity, not benignity.
BP1	Not met	GBA1 missense variants are a well-established cause of both autosomal recessive Gaucher disease and Parkinson's disease risk. The gene is not one in which only truncating variants cause disease.	cspec
BP2	Not met	GBA1 is associated with autosomal recessive Gaucher disease. No observation of this variant in cis with a pathogenic variant in a healthy individual, or in trans with a pathogenic variant for a fully penetrant dominant disorder, was identified to support BP2. Exploratory search suggests the variant may be observed in trans with pathogenic alleles in Gaucher disease patients (PMID:9375849), which would support pathogenicity rather than benignity.
BP3	N/A	BP3 applies to in-frame insertions/deletions in repetitive regions; NM_000157.4:c.1279G>A is a single-nucleotide substitution (missense).
BP4	Not met	Multiple lines of computational evidence do not consistently suggest no impact. While BayesDel (0.107) is benign-leaning and SpliceAI (max delta 0.07) predicts no splicing impact, REVEL (0.579) is intermediate and does not clearly support a benign interpretation. The computational evidence is mixed rather than consistently benign.	revel bayesdel spliceai
BP5	Not assessed	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	Not met	ClinVar reports this variant as Uncertain significance (7 clinical laboratories). No reputable source has reported the variant as benign or likely benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. NM_000157.4:c.1279G>A is a missense variant (p.Glu427Lys), not a synonymous variant.

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