rs1141812
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_000157.4(GBA1):c.247C>T(p.Arg83Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000589 in 1,613,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000062 ( 0 hom. )
Consequence
GBA1
NM_000157.4 missense
NM_000157.4 missense
Scores
2
9
7
Clinical Significance
Conservation
PhyloP100: 3.47
Genes affected
GBA1 (HGNC:4177): (glucosylceramidase beta 1) This gene encodes a lysosomal membrane protein that cleaves the beta-glucosidic linkage of glycosylceramide, an intermediate in glycolipid metabolism. Mutations in this gene cause Gaucher disease, a lysosomal storage disease characterized by an accumulation of glucocerebrosides. A related pseudogene is approximately 12 kb downstream of this gene on chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2010]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000157.4
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.18886441).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GBA1 | NM_000157.4 | c.247C>T | p.Arg83Cys | missense_variant | 3/11 | ENST00000368373.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GBA1 | ENST00000368373.8 | c.247C>T | p.Arg83Cys | missense_variant | 3/11 | 1 | NM_000157.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152118Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000836 AC: 21AN: 251312Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135836
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GnomAD4 exome AF: 0.0000622 AC: 91AN: 1461872Hom.: 0 Cov.: 33 AF XY: 0.0000495 AC XY: 36AN XY: 727236
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152118Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3AN XY: 74316
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 22, 2021 | Reported previously using alternate nomenclature (R44C) in an Ashkenazi Jewish (AJ) individual with essential tremor; however, the authors concluded that there was no evidence for association of GBA variants with essential tremor as the variants were present with similar frequencies in AJ essential tremor patients and AJ controls (Clark et al., 2010); Reported in the heterozygous state in two individuals with Parkinson disease and was absent in controls. One of the individuals was a Parkinson disease patient with no family history who also harbored a variant in the LRRK2 gene (Benitez et al., 2016); In an Ashkenazi Jewish population screening study for GBA variants in Parkinson patients, the frequency of the R83C (reported as R44C) variant was 4 times higher in an in-house control population (7/662) than in the Parkinson disease patient population (2/735); however, the variant was present at a lower frequency in a larger control population derived from the IBD exomes project, suggesting that further studies are needed to better understand the significance of this variant (Ruskey et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in nearby residues reported in the Human Gene Mutation Database in individuals with Gaucher disease and Parkinson disease (Stenson et al., 2014) This variant is associated with the following publications: (PMID: 31996268, 29842932, 19815695, 19527940, 27094865, 26117366, 21837367) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2017 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 18, 2021 | Variant summary: GBA c.247C>T (p.Arg83Cys), also known as R44C in literatures, results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-05 in 258476 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in GBA causing Gaucher Disease (8.5e-05 vs 0.005), allowing no conclusion about variant significance. c.247C>T has been reported in the literature in individuals affected with essential tremor, Amyotrophic lateral sclerosis, Dementia with Lewy bodies and Parkinson's disease (Clark_2009, Gan-Or2011, Alcalay_2015, Mata_2016, Benitez_2016, Kruger_2016, Robak_2017, Goldstein_2019, Orme_2020, Mangone_2020). These reports do not provide unequivocal conclusions about association of the variant with disease. Additionally, other missense variants (p.R78H, p.S81N,p.G85E, p.T100M) in nearby residues have been found in individuals affected with Gaucher disease and Parkinson's disease in the Human Gene Mutation Database. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Gaucher disease type II;C0268251:Gaucher disease type III;C0752347:Lewy body dementia;C1842704:Gaucher disease perinatal lethal;C1856476:Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;C1961835:Gaucher disease type I;C3160718:Parkinson disease, late-onset Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 03, 2022 | - - |
Gaucher disease Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 09, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Benign
DEOGEN2
Pathogenic
D;D;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M
MutationTaster
Benign
N;N;N;N;N
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;D;.
Vest4
MVP
MPC
0.14
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at