Submissions for variant NM_000157.4(GBA1):c.1093G>A (p.Glu365Lys)

gnomAD frequency: 0.01061  dbSNP: rs2230288

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000252989	SCV000232999	benign	not specified	2014-11-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000252989	SCV000305636	benign	not specified		criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414984	SCV000492833	risk factor	Parkinsonian disorder; 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	Parkinsonian disorder; Abnormal speech pattern; 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	Parkinsonian disorder	2014-02-17	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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 Center for Human Genetics Tuebingen	RCV000487503	SCV000574790	benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	GBA1: BS1, BS2
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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248923	SCV001422690	benign	Gaucher disease	2020-01-22	criteria provided, single submitter	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).
Fulgent Genetics, Fulgent Genetics	RCV001836745	SCV001652785	risk factor	Parkinson disease, late-onset	2021-05-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001509572	SCV001716345	likely benign	Gaucher disease perinatal lethal	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000487503	SCV001941268	benign	not provided	2018-09-12	criteria provided, single submitter	clinical testing	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)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000487503	SCV002048522	benign	not provided	2021-09-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000487503	SCV003244248	benign	not provided	2022-08-23	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001509572	SCV005086522	uncertain significance	Gaucher disease perinatal lethal	2023-07-17	criteria provided, single submitter	clinical testing	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
Mayo Clinic Laboratories, Mayo Clinic	RCV000487503	SCV000800927	uncertain significance	not provided	2024-01-19	no assertion criteria provided	clinical testing	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.
Natera, Inc.	RCV001248923	SCV001455161	benign	Gaucher disease	2020-04-23	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000487503	SCV001744809	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000252989	SCV001808045	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000487503	SCV001928214	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000487503	SCV001964892	likely benign	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV001248923	SCV002586407	not provided	Gaucher disease		no assertion provided	literature only