ClinVar Miner

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

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000413257 SCV000692643 likely pathogenic not provided 2017-10-31 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; Abnormality of movement 2017-01-01 criteria provided, single submitter clinical testing
Counsyl RCV000004511 SCV000485111 pathogenic Gaucher's disease, type 1 2016-02-09 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000413257 SCV000111209 pathogenic not provided 2017-02-23 criteria provided, single submitter clinical testing
Foundation for Research in Genetics and Endocrinology,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.
Foundation for Research in Genetics and Endocrinology,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.
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.
GeneReviews RCV000020150 SCV000040477 pathologic Gaucher disease 2011-02-01 no assertion criteria provided curation Converted during submission to Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000020150 SCV000697583 pathogenic Gaucher disease 2016-01-18 criteria provided, single submitter clinical testing
Invitae RCV000413257 SCV000964136 pathogenic not provided 2019-01-16 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).  ClinVar contains an entry for this variant (Variation ID: 4288, 4297). This variant is also known as p.Leu444Pro in the literature. Experimental studies have shown that this missense change impairs GBA enzyme activity (PMID: 8294487, 15146461, 24020503). The observation of one or more missense substitutions downstream of this variant (p.Leu483Pro, p.Leu483Arg) in affected individuals suggests that this may be a clinically significant region of the GBA protein (PMID: 7981693). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000413257 SCV000800923 pathogenic not provided 2015-12-15 no assertion criteria provided 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

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