ClinVar Genomic variation as it relates to human health

The p.Ser146Leu variant in GBA has been reported in 7 individuals with Gaucher Disease (PMID: 15329082, 30949558; doi:10.4172/2167-0889.1000122) and has been identified in 0.006% (7/113742) of European (non-Finnish) chromosomes and 0.006% (1/16254) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs758447515). 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: 197702) as a VUS 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. The presence of this variant in combination with reported pathogenic variants in 6 individuals with Gaucher Disease increases the likelihood that the p.Ser146Leu variant is pathogenic (VariationID: 4290; PMID: 30949558; doi:10.4172/2167-0889.1000122). The p.Ser146Leu variant is located in the catalytic domain of GBA, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 30949558). The phenotype of individuals compound heterozygous for this variant is highly specific for Gaucher Disease based on low glucocerebrosidase activity consistent with disease (PMID: 15329082; doi:10.4172/2167-0889.1000122). 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 combination with other pathogenic variants, the variant being located in a functional domain, and the phenotype of an individual with the variant being highly specific for Gaucher Disease. ACMG/AMP Criteria applied: PM3_strong, PM2, PM1, PP3, PP4 (Richards 2015).

Previously reported in the heterozygous state in an individual with Parkinson disease (Pakarulrazy et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27836528, 27789132, 9516376, 24262167, 32165122, 10744424, 12970647, 25567624, 15329082, 27816428, 23056756, 10649495, 34072542, 27872820, 9554454, 30949558, Pakarulrazy2020[article], 22247978, 32658388, 33473340)

The p.S146L variant (also known as c.437C>T and S107L), located in coding exon 4 of the GBA gene, results from a C to T substitution at nucleotide position 437. The serine at codon 146 is replaced by leucine, an amino acid with dissimilar properties. This variant was detected in conjunction with a pathogenic GBA alteration in individuals with type 1 and type 2 Gaucher disease; however, phase of the alterations was not confirmed (Demina A et al. Acta Haematol., 1998;99:80-2; Machaczka M et al. Ups. J. Med. Sci., 2012 Mar;117:28-34; Ortiz-Cabrera NV et al. Mol Genet Metab Rep, 2016 Dec;9:79-85). In our internal cohort, this variant was detected in an obligate carrier with a history of two affected pregnancies with the perinatal-lethal form of Gaucher disease. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.