ClinVar Genomic variation as it relates to human health

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.

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 483 of the GBA protein (p.Leu483Arg). This variant is present in population databases (rs421016, gnomAD 0.006%). This missense change has been observed in individual(s) with Gaucher disease (PMID: 7981693, 27825739). This variant is also known as L444R. ClinVar contains an entry for this variant (Variation ID: 93449). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GBA protein function with a positive predictive value of 80%. 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: 8294487, 15146461, 24020503, 26096741). 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.

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000093449, PS1_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000004288, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.891, 3CNET: 0.997, PP3_P). A missense variant is a common mechanism associated with Gaucher disease (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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, http://gnomad.broadinstitute.org; 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).

This variant is also referred to as L444R in the literature. It has been previously reported as a heterozygous and compound heterozygous change in patients with GBA-related disorders (PMID: 27825739, 7981693, 26043810, 31077260, 27717005). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0007% (2/250058) and thus is presumed to be rare. The c.1448T>G (p.Leu483Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1448T>G (p.Leu483Arg) variant is classified as Pathogenic.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(L444R); This variant is associated with the following publications: (PMID: 34951095, 34867278, 24278166, 10649495, 26043810, 28003644, RiboldiGM2019[review], 31912918, 27717005, 31077260, 35885615, 38053927, 25909086, 36256599, 36334031, 35242582, 36220738, 35562809, 32613234, 35639160, 38474117, 27825739, 7981693)

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.