ClinVar Miner

Submissions for variant NM_000157.3(GBA):c.1448T>C (rs421016)

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Total submissions: 22
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000413257 SCV000111209 pathogenic not provided 2017-02-23 criteria provided, single submitter clinical testing
GeneDx RCV000413257 SCV000491300 pathogenic not provided 2018-12-25 criteria provided, single submitter clinical testing The L483P variant is a common variant in the GBA gene and has been reported previously using alternate nomenclature L444P. The L483P variant has been frequently identified in the homozygous and compound heterozygous states in individuals with Gaucher disease (Tsuji et al., 1987; Malini et al., 2014; Mhanni et al., 2016). The L483P variant has also been identified in the heterozygous state in patients with Lewy body dementia and with Parkinson disease with dementia, however, L483P was also identified in the heterozygous state in control individuals used in these studies (Mata et al., 2008; Nalls et al., 2013). The L483P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Functional studies of L483P indicate that it is poorly activated by phosphatidylserine, has residual enzyme activity of 5-10% of wild type, and is unstable (Grace et al., 1994; Malini et al., 2014). We interpret L483P as a pathogenic variant.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000413257 SCV000692643 pathogenic not provided 2020-03-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000020150 SCV000697583 pathogenic Gaucher disease 2016-01-18 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626625 SCV000747326 risk factor Hypomimic face; Parkinsonism; Resting tremor; Thoracolumbar scoliosis; Movement disorder 2017-01-01 criteria provided, single submitter clinical testing
Invitae RCV000413257 SCV000964136 pathogenic not provided 2020-01-06 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 483 of the GBA protein (p.Leu483Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. The frequency data for this variant in the population databases (rs421016, ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has been observed in several individuals affected with Gaucher disease (PMID: 26096741, 8929950, 22713811), Parkinson's disease (PMID: 25249066, 27094865, 20816920, 25535748, 18987351, 23676350), and dementia with Lewy bodies (PMID: 23588557). This variant is also known as p.Leu444Pro in the literature. ClinVar contains an entry for this variant (Variation ID: 4288, 4297). Experimental studies have shown that this missense change impairs GBA enzyme activity (PMID: 8294487, 15146461, 24020503). This variant disrupts the p.Leu483 amino acid residue in GBA. Other variant(s) that disrupt this residue have been observed in individuals with GBA-related conditions (PMID: 7981693), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics,Klinikum rechts der Isar RCV000004512 SCV001150114 pathogenic Parkinson disease, late-onset 2018-07-19 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004112 SCV001162843 pathogenic Gaucher's disease, type 1; Acute neuronopathic Gaucher's disease; Subacute neuronopathic Gaucher's disease; Gaucher disease type 3C criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000004511 SCV001194224 pathogenic Gaucher's disease, type 1 2019-10-30 criteria provided, single submitter clinical testing NM_001005741.2(GBA):c.1448T>C(L483P, aka L444P) is classified as pathogenic in the context of Gaucher disease. The L483P variant can be associated with either Type 1, 2 or 3 Gaucher disease. Sources cited for classification include the following: PMID 2880291, 15146461, 21106416, 27123474 and 9375849. Classification of NM_001005741.2(GBA):c.1448T>C(L483P, aka L444P) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197030 SCV001367665 pathogenic Cognitive impairment; Parkinsonism; Resting tremor 2018-11-02 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PVS1,PM2. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197164 SCV001367800 pathogenic Inborn errors of metabolism 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP2. This variant was detected in heterozygous state.
Centogene AG - the Rare Disease Company RCV000020150 SCV001424427 pathogenic Gaucher disease criteria provided, single submitter clinical testing
OMIM RCV000004509 SCV000024683 pathogenic Acute neuronopathic Gaucher's disease 2013-10-01 no assertion criteria provided literature only
OMIM RCV000004510 SCV000024684 pathogenic Subacute neuronopathic Gaucher's disease 2013-10-01 no assertion criteria provided literature only
OMIM RCV000004511 SCV000024685 pathogenic Gaucher's disease, type 1 2013-10-01 no assertion criteria provided literature only
OMIM RCV000004512 SCV000024686 risk factor Parkinson disease, late-onset 2013-10-01 no assertion criteria provided literature only
OMIM RCV000004513 SCV000024687 risk factor Dementia, Lewy body, susceptibility to 2013-10-01 no assertion criteria provided literature only
GeneReviews RCV000020150 SCV000040477 pathologic Gaucher disease 2011-02-01 no assertion criteria provided curation Converted during submission to Pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000004509 SCV000786647 likely pathogenic Acute neuronopathic Gaucher's disease 2018-06-29 no assertion criteria provided clinical testing The observed variant c.1448T>C (p.Leu483Pro) has a minor allele frequency of 0.0034 in 1000 Genomes and 0.003099 in ExAC databases. The in silico prediction of the given variant is disease causing by MutationTaster2, damaging by SIFT and possibly damaging by PolyPhen2. This variant was detected as a compound heterozygous along with another variant c.1448T>G (p.Leu483Arg). The variant c.1448T>G (p.Leu483Arg) was neither found in 1000 Genomes and ExAC databases. The in silico prediction of the given variant is disease causing by MutationTaster2, damaging by SIFT and probably damaging by PolyPhen2.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000413257 SCV000800923 pathogenic not provided 2015-12-15 no assertion criteria provided clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000004511 SCV000864168 pathogenic Gaucher's disease, type 1 2019-01-03 no assertion criteria provided clinical testing The variant NM_000157.4: c.1448T>C(p.L483P) in exon-10 of GBA gene has been seen in heterozygous status. It is the most common mutation in Indian patients affected with Gaucher's Disease.
Broad Institute Rare Disease Group,Broad Institute RCV000020150 SCV001422763 pathogenic Gaucher disease 2020-01-22 no assertion criteria provided curation The p.Leu483Pro variant in GBA has been reported in at least 89 individuals with Gaucher disease (PMID: 17427031, 23719189, 30662625) and has been identified in 0.245% (25/10202) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs421016). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role and is consistent with the increased prevalence of Gaucher disease in the Ashkenazi Jewish population. This variant has also been reported in ClinVar (VariationID: 4288) as pathogenic by EGL Genetic Diagnostics, Counsyl, GeneDx, Integrated Genetics, Mayo Clinic Genetic Testing Laboratories, Foundation for Research in Genetics and Endocrinology, and OMIM and as likely pathogenic by Praxis fuer Humangenetik Tuebingen. Animal models in mice have shown that this variant causes Gaucher disease (PMID: 28686011). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Leu483Arg, has been reported in association with disease in the literature and ClinVar, raising the possibility that a change at this position may not be tolerated (VariationID: 93449; PMID: 27825739). The phenotype of 11 individuals homozygous or compound heterozygous for this variant is highly specific for Gaucher Disease based on beta-glucosidase residual activity <10% of normal, consistent with disease (PMID: 30662625, 23719189). The presence of this variant in 16 affected homozygotes and in combination with reported pathogenic variants (VariationID: 4290, 4293, 4327, 21070, 193611, 4314; PMID: 17427031, 23719189, 30662625) in 67 individuals with Gaucher disease increases the likelihood that the p.Leu483Pro variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on the presence of the variant in affected individuals and in combination with other pathogenic variants, functional studies, and the phenotype of individuals with this variant being highly specific for Gaucher disease. ACMG/AMP Criteria applied: PM3_very-strong, PS3, PP3, PP4 (Richards 2015).

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