ClinVar Miner

Submissions for variant NM_000157.4(GBA):c.1093G>A (p.Glu365Lys) (rs2230288)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 13
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000252989 SCV000232999 benign not specified 2014-11-14 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000252989 SCV000305636 benign not specified criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414984 SCV000492833 risk factor Parkinsonism; Tremor; Rigidity; Cogwheel rigidity 2014-12-12 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415387 SCV000492849 risk factor Parkinsonism; Neurological speech impairment; Hyperlipidemia; Lower limb muscle weakness; Dementia; Hypertensive disorder 2014-06-19 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415149 SCV000492891 risk factor Parkinsonism 2014-02-17 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000252989 SCV000539226 benign not specified 2016-06-02 criteria provided, single submitter clinical testing 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
CeGaT Praxis fuer Humangenetik Tuebingen RCV000487503 SCV000574790 uncertain significance not provided 2020-08-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000252989 SCV000697574 likely benign not specified 2020-05-25 criteria provided, single submitter clinical testing 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.
Fulgent Genetics,Fulgent Genetics RCV001449605 SCV001652785 risk factor Hereditary late onset Parkinson disease 2021-05-03 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV001509572 SCV001716345 likely benign Gaucher disease, perinatal lethal 2021-05-18 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000487503 SCV000800927 uncertain significance not provided 2017-08-02 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV001248923 SCV001422690 benign Gaucher disease 2020-01-22 no assertion criteria provided curation 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).
Natera, Inc. RCV001248923 SCV001455161 benign Gaucher disease 2020-04-23 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.