ClinVar Miner

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

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Total submissions: 24
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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 2020-01-13 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect indicating that this variant is poorly activated by phosphatidylserine, is unstable and has residual enzyme activity of 5-10% of wild type (Grace et al., 1994; Malini et al., 2014); 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); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Previously reported as L444P due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 21472771, 21106416, 8294487, 31561936, 23286447, 23227814, 23642305, 21700325, 21700212, 21856586, 22220748, 23635853, 24022302, 22713811, 23783781, 22975760, 20643691, 15146461, 22623374, 23588557, 16293621, 22006919, 25333069, 21742527, 21745757, 22227073, 20131388, 23676350, 24126159, 20004703, 20816920, 18347322, 18987351, 24020503, 25535748, 22160715, 23277556, 22192918, 25249066, 21228398, 8607360, 2880291, 27014572, 18332251, 27094865, 26096741, 27717005, 27153395, 19846850, 27865684, 16967369, 29934114, 11336129, 29625627, 24195576, 29602947, 29140481, 29396846, 28894968, 28003644, 8929950, 10714667, 24095219, 8160756, 30146349, 30548430, 27896091, 29842932, 30537300, 29029963, 29487000, 31193028, 30941926, 30606667, 31216804, 30456712, 31130284, 29471591, 33083013, 32618053, 32883051, 33763395, 33176831, 32658388)
CeGaT Praxis fuer Humangenetik Tuebingen RCV000413257 SCV000692643 pathogenic not provided 2021-06-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000020150 SCV000697583 pathogenic Gaucher disease 2021-04-15 criteria provided, single submitter clinical testing Variant summary: GBA c.1448T>C (p.Leu483Pro) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, beta sandwich domain (IPR033452) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0013 in 250058 control chromosomes (gnomAD). c.1448T>C has been reported in the literature in multiple individuals affected with Gaucher Disease (Miocic_ 2005, Malini_2013, Siebert_2013, Tammachote_2013). These data indicate that the variant is very likely to be associated with disease. Functional studies report the variant effect results in decreasing GBA enzyme activity in transfected cells (Alfonso__2004, Malini_2013). 12 ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=11) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
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
Mayo Clinic Laboratories, Mayo Clinic RCV000413257 SCV000800923 pathogenic not provided 2019-07-15 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.
Baylor Genetics RCV001004112 SCV001162843 pathogenic Gaucher disease type I; Gaucher disease type II; Gaucher disease type III; Gaucher disease type 3C criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000004511 SCV001194224 pathogenic Gaucher disease type I 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 RCV001197164 SCV001367800 pathogenic Gaucher disease, perinatal lethal 2018-11-02 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM5,PP3,PP5,PS1,PS3.
Centogene AG - the Rare Disease Company RCV000020150 SCV001424427 pathogenic Gaucher disease criteria provided, single submitter clinical testing
Baylor Genetics RCV000004509 SCV001520375 pathogenic Gaucher disease type II 2020-07-07 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Fulgent Genetics,Fulgent Genetics RCV001449607 SCV001652787 pathogenic Hereditary late onset Parkinson disease 2021-05-03 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000004511 SCV001653493 pathogenic Gaucher disease type I 2021-05-18 criteria provided, single submitter clinical testing
OMIM RCV000004509 SCV000024683 pathogenic Gaucher disease type II 2013-10-01 no assertion criteria provided literature only
OMIM RCV000004510 SCV000024684 pathogenic Gaucher disease type III 2013-10-01 no assertion criteria provided literature only
OMIM RCV000004511 SCV000024685 pathogenic Gaucher disease type I 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 Gaucher disease type II 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.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000004511 SCV000864168 pathogenic Gaucher disease type I 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.
Institute of Human Genetics, Klinikum rechts der Isar RCV000004512 SCV001150114 pathogenic Parkinson disease, late-onset 2018-07-19 no assertion criteria provided clinical testing
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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