ClinVar Miner

Submissions for variant NM_000157.4(GBA):c.1448T>G (p.Leu483Arg) (rs421016)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414719 SCV000491299 likely pathogenic not provided 2016-04-11 criteria provided, single submitter clinical testing The L483R variant in the GBA gene has been reported previously (as L444R due to the use of alternative nomenclature) in association with Gaucher disease (Uchiyama et al., 1994; Rolfs et al., 2013). This variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L483R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at the same (L483P) and nearby (D482N, A485P, V486E) residues have been reported in the Human Gene Mutation Database in association with Gaucher disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. The L483R variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000414719 SCV000700297 pathogenic not provided 2013-09-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781411 SCV000919418 pathogenic Gaucher disease 2020-05-07 criteria provided, single submitter clinical testing Variant summary: GBA c.1448T>G (p.Leu483Arg), also widely reported as p.Leu444Arg, results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, beta sandwich domain 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 8e-06 in 250058 control chromosomes. c.1448T>G has been reported in the literature in multiple individuals affected with Gaucher Disease (example, Basgalupp_2018, Uchiyama_1994, Smith_2016, Wilke_2019) and in association with Parkinson disease among carriers of Gaucher Disease (example, Liu_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1)/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV001004111 SCV001162842 likely pathogenic Gaucher disease type I; Gaucher disease type II; Gaucher disease type III; Gaucher disease type 3C criteria provided, single submitter clinical testing
Invitae RCV000414719 SCV001208546 pathogenic not provided 2020-08-14 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 483 of the GBA protein (p.Leu483Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Gaucher disease (PMID: 27825739, 7981693). This variant is also known as L444R in the literature. ClinVar contains an entry for this variant (Variation ID: 93449). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Leu483 amino acid residue in GBA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26096741, 8294487, 15146461, 24020503). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000663363 SCV000786646 likely pathogenic Gaucher disease type II 2018-06-29 no assertion criteria provided clinical testing The observed 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. This variant was detected as a compound heterozygous along with another variant c.1448T>C (p.Leu483Pro) in exon 10 of GBA gene. The variant c.1448T>C (p.Leu483Pro) has a minor allele frequency of 0.0034 in 1000 Genomes and 0.003099 in ExAC databases. Its dbSNP reference number is rs421016. The in silico prediction of the given variant is disease causing by MutationTaster2, damaging by SIFT and possibly damaging by PolyPhen2.
Broad Institute Rare Disease Group, Broad Institute RCV001248963 SCV001422764 likely pathogenic Gaucher disease type I 2020-01-22 no assertion criteria provided curation The p.Leu483Arg variant in GBA has been reported in two Brazilian individuals with Gaucher disease (PMID: 27825739) and has been identified in 0.005% (1/18388) of East Asian chromosomes and 0.003% (1/34386) of Latino chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs421016). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 93449) as likely pathogenic by GeneDx, Integrated Genetics, and the Foundation for Research In Genetics and Endocrinology, and as pathogenic by EGL Genetic Diagnostics. 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 pathogenic variant, resulting in a different amino acid change at the same position, p.Leu483Pro, has been reported in association with disease in ClinVar and the literature, supporting that a change at this position may not be tolerated (VariationID: 4288; PMID: 17427031, 23719189, 30662625, 28686011). The presence of this variant in combination with a reported pathogenic variant and in 2 individuals with Gaucher disease increases the likelihood that the p.Leu483Arg variant is pathogenic (VariationID: 4290, PMID: 27825739). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM5, PM3, PP3 (Richards 2015).

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