chr1-155236376-C-T
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Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_000157.4(GBA1):c.1093G>A(p.Glu365Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,614,092 control chromosomes in the GnomAD database, including 196 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,risk factor (no stars).
Frequency
Genomes: 𝑓 0.010 ( 23 hom., cov: 32)
Exomes 𝑓: 0.013 ( 173 hom. )
Consequence
GBA1
NM_000157.4 missense
NM_000157.4 missense
Scores
1
5
12
Clinical Significance
Conservation
PhyloP100: 0.321
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 Benign. Variant got -11 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.110501975).
BP6
Variant 1-155236376-C-T is Benign according to our data. Variant chr1-155236376-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity, risk_factor]. Clinvar id is 199044.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, risk_factor=4, not_provided=1, Benign=8, Uncertain_significance=1}. Variant chr1-155236376-C-T is described in Lovd as [Likely_benign]. Variant chr1-155236376-C-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0101 (1540/152250) while in subpopulation NFE AF= 0.0128 (868/67984). AF 95% confidence interval is 0.0121. There are 23 homozygotes in gnomad4. There are 843 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 23 AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| GBA1 | NM_000157.4 | c.1093G>A | p.Glu365Lys | missense_variant | 8/11 | ENST00000368373.8 | NP_000148.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| GBA1 | ENST00000368373.8 | c.1093G>A | p.Glu365Lys | missense_variant | 8/11 | 1 | NM_000157.4 | ENSP00000357357 | P1 |
Frequencies
GnomAD3 genomes 0.0101 AC: 1541AN: 152132Hom.: 23 Cov.: 32
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GnomAD3 exomes AF: 0.0105 AC: 2630AN: 251434Hom.: 34 AF XY: 0.0102 AC XY: 1387AN XY: 135894
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GnomAD4 exome AF: 0.0125 AC: 18333AN: 1461842Hom.: 173 Cov.: 33 AF XY: 0.0121 AC XY: 8795AN XY: 727234
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GnomAD4 genome 0.0101 AC: 1540AN: 152250Hom.: 23 Cov.: 32 AF XY: 0.0113 AC XY: 843AN XY: 74442
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ClinVar
Significance: Conflicting classifications of pathogenicity; risk factor
Submissions summary: Uncertain:2Benign:15Other:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:7
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 12, 2018 | This variant is associated with the following publications: (PMID: 21700325, 11903352, 15146461, 22623374, 16293621, 21742527, 21831682, 22227325, 18987351, 22001711, 27094865, 27571329, 27312774, 26000814, 28030538, 26296077, 27153395, 1864608, 28834018, 28830825, 29140481, 30302829, 30146349, 29842932, 29487000, 30777654, 24022302, 23225227, 31996268, 32618053, 32658388) - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 23, 2022 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 19, 2024 | The heterozygous c.1093G>A (p.Glu365Lys) missense variant in the GBA1 gene (MIM:606463) is classified as a variant of uncertain significance. Pathogenic variants in the GBA1 gene have been associated with autosomal recessive Gaucher disease. This variant has been reported previously in the literature as a modifier variant or very mild variant (PMID 24022302; PMID 21831682). This variant has also been reported at a higher frequency in patients with Parkinson's disease as compared to controls with an odds ratio of 1.65-5.5 (PMID 29842932; PMID 32618053; PMID 27571329; PMID 26296077; PMID 27094865; PMID 28830825; PMID 32853481). Expression studies from several groups showed an average enzyme activity between 39% and 54% of wild type constructs (PMID 24022302; PMID 21831682). This level of activity reduction is not sufficient to cause Gaucher disease when in trans to another pathogenic GBA mutation. The overall minor allele frequency for this variant (rs2230288) is approximately 1.073% with a frequency up to 4.325% in Finnish sub-populations. This amino acid is moderately conserved across species and an in silico meta-predictor is inconclusive as to whether this amino acid change impacts protein function. Taken together, the evidence is not sufficient to determine whether this variant is a hypomorphic allele or is associated with increased risk for Parkinson's disease. - |
| Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | GBA1: BS1, BS2 - |
| Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 28, 2021 | - - |
not specified Benign:5
| Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 14, 2014 | - - |
| Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 02, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 0.97% in ExAC, 4.3% in Finnish, 12 hom - |
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 25, 2020 | Variant summary: GBA c.1093G>A (p.Glu365Lys) results in a conservative amino acid change located in the Glycosyl hydrolase family 30, TIM-barrel domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.01 in 252724 control chromosomes, predominantly at a frequency of 0.012 within the Non-Finnish European subpopulation in the gnomAD database, including 11 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in GBA causing Gaucher Disease phenotype (0.005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1093G>A has been reported in the literature in individuals affected with Gaucher Disease. This variant did not co-segregate with disease in at-least one family with a clinical diagnosis of Gaucher's disease. Specifically, while two affected siblings were compound heterozygous for G202R and L444P, the healthy father carried this variant in compound heterozygous state with G202R, further supporting non-pathogenic role (Zhao_2003). This variant has been reported in many GD patients, all within a complex allele with another variant in cis (such as D140H+E326K, N188S+E326K, and L444P+E326K), and the variant alone has not been reported in any GD patients. This variant has also been reported in many PD patients, and has been suggested to be modestly increase risk for PD with borderline odds ratios (OR) by multiple studies in Europeans, including a GWAS study (Nichols_2009, Lesage_2011, Pankratz_2012, Durhan_2013, Ran_2016, Mata_2016). Meanwhile, there are other conflicting case-control studies that do not show this variant as a significant risk allele for PD (Bras_2009, Alcalay_2015, Han_2016). Multiple functional studies show that the variant alone could lead to 30-60% of wild-type enzymatic activity and the complex alleles show much lower activities than the each of the single variant alone, suggesting an additive effect. However, in at-least one reported instance, the specific activity of the complex allele E326K+L444P was not different from that of L444P alone in a study where a genotype of E326K+L444P and E233X in trans was reported in a patient with a severe neonatal type 2 course (Grace_1999). This points to L444P being more penetrant relative to E326K in this patient. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. While one clinical diagnostic laboratory has classified this variant as benign and two have classified it as uncertain significance. Another lab classified it as risk factor before 2014, all without evidence for independent evaluation. Taken together, in context of Gaucher disease, this variant alone is likely not disease-causing; however, it can possibly increase the functional defect of another GBA variant in cis. In context of Parkinsons disease, this variant may be a mild risk allele. Since this variant does not confer a considerable or clinically significant risk for Parkinsons disease and does not cause Gaucher disease, it is classified as likely benign in line with its role as functional polymorphism. - |
| Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Gaucher disease Benign:2Other:1
| Benign, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The p.Glu365Lys variant in GBA has been reported in at least 14 individuals with Gaucher disease (PMID: 15967693, 23225227, 29980418, 11903352) and has been identified in 4.325% (1086/25110) of European (Finnish) chromosomes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs2230288). This variant has also been reported in ClinVar (VariationID: 199044) as likely benign by Integrated Genetics, as a VUS by Mayo Clinic Genetic Testing Laboratories and Praxis fuer Humangenetik Tuebingen, and as benign by Laboratory for Molecular Medicine, EGL Genetic Diagnostics, and University Medical Centre Ljubljana. The p.Glu365Lys variant did not segregate with Gaucher disease in 2 affected relatives of an individual with the variant, suggesting that this variant is not pathogenic for Gaucher disease (PMID: 12791040). In vitro functional studies demonstrating that the variant alone reduces enzyme activity only to the lower level of the normal range, about 42% of wild-type, provide some evidence that the p.Glu365Lys variant may not impact protein function when not part of a complex allele. Additional functional studies have shown that the variant leads to further reduction of enzyme activity when in cis with other pathogenic variants, suggesting that the variant may increase disease severity when in cis with a pathogenic variant (PMID: 15967693, 23225227, 22227325). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant was found in cis with another pathogenic variant in every Gaucher disease patient found to carry the variant, suggesting that it may not cause disease (VariationID: 4288, 4290, 4314; PMID: 15967693, 23225227, 29980418, 11903352). In summary, this variant meets criteria to be classified as benign for Gaucher disease in an autosomal recessive manner--but is expected to increase disease severity as part of a complex allele--based on the high frequency of the variant in the general population, nonsegregation of the variant with disease, the presence of the variant in cis with pathogenic variants in affected individuals, and in vitro functional studies. ACMG/AMP Criteria applied: BS1, BS4, BP2, BS3_supporting (Richards 2015). - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 23, 2020 | - - |
Gaucher disease perinatal lethal Uncertain:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Gaucher disease (MIM# 230800, 230900, 231000, 231005, 608013). (I) 0106 - This gene is associated with autosomal recessive disease. The different types of Gaucher disease are considered to fall within a spectrum, rather than distinct conditions, and are determined by age of disease onset and the presence and severity of neurologic function. Specific counseling about individual case prognosis is hindered by a significant overlap in the clinical features of individuals with various genotypes (OMIM, PMID: 20301446). (I) 0115 - Variants in this gene are known to have variable expressivity. Gaucher disease is associated with marked clinical variability, even within the same family (PMID: 31010158). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0306 - Variant is present in gnomAD (v2) >=0.03 and <0.05 for a recessive condition (1961 heterozygotes, 37 homozygotes). (I) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated glycosol hydrolase family 20 TIM-barrel domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been classified as benign, likely benign, a VUS and a risk factor by clinical laboratories in ClinVar, and has been observed in cis with three different missense variants in individuals with Gaucher disease where it is described as part of a complex allele (PMIDs: 1864608, 10079102, 15146461). (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant by itself has been shown to have between 40 and 60% of normal enzyme activity, but when it is part of a complex allele with other variants this results in enzyme activity of between 3-20%. When this complex allele involves p.(Asp179His) or p.(Asn188Ser) this combination lowers the enzyme activity below what either variant alone retains, but this difference is minimal when the complex allele involves p.(Leu444Pro) (PMIDs: 10079102, 15146461). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Parkinson disease, late-onset Other:1
| risk factor, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 03, 2021 | - - |
Hyperlipidemia;C0020538:Hypertensive disorder;C0242422:Parkinsonian disorder;C0497327:Dementia;C1836296:Lower limb muscle weakness;C3687424:Abnormal speech pattern Other:1
| risk factor, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jun 19, 2014 | - - |
Parkinsonian disorder Other:1
| risk factor, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Feb 17, 2014 | - - |
Rigidity;C0040822:Tremor;C0151564:Cogwheel rigidity;C0242422:Parkinsonian disorder Other:1
| risk factor, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Dec 12, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
.;T;T;T
MetaRNN
Benign
T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;.;.
MutationTaster
Benign
A;A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T;T
Sift4G
Benign
T;T;T;T
Polyphen
B;B;.;.
Vest4
MPC
0.86
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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