ClinVar Genomic variation as it relates to human health

Variant summary: GBA c.1240G>T (p.Val414Leu, legacy name V375L) results in a conservative amino acid change located in the Glycosyl hydrolase family 30, TIM-barrel domain (IPR033453) of the encoded protein sequence. Another variant, c.1240G>C (p.Val414Leu) has also been ascertained in the context of this evaluation. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251476 control chromosomes. c.1240G>T and c.1240G>C have been reported in the literature in multiple individuals affected with Gaucher Disease (example, Cormand_1997, Kleinotiene_2011, Chen_2005, Gupta_2011, Gonzalez_2013). This variant has been subsequently cited by others as a mild mutation associated with Gaucher Disease (example Cormand_1997, Beutler_1998, Beutler_2005, Hruska_2008 and Shamseddine_2004). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity in leukocytes with limited material available for further enzymatic characterization (Cormand_1997). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Although one submitter has classified the variant as likely pathogenic before 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

The p.Val414Leu variant in GBA has been reported in 8 individuals with Gaucher disease (PMID: 27865684, 19026343, 9182788, 29685539, 15954102) and has been identified in 0.001% (1/113754) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs398123528). 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: 93448) as likely 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. Additionally, the presence of this variant in the homozygous state in two individuals with Gaucher disease and in combination with reported pathogenic variants (VariationID: 93459, 4288; PMID: 19026343, 29685539) in two individuals with Gaucher disease increases the likelihood that the p.Val414Leu variant is pathogenic. The phenotype of an individual homozygous for this variant is highly specific for Gaucher disease based on B-glucosidase activity levels below 8.7 nmol/h/mg protein, consistent with disease (PMID: 9182788, 27865684). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_strong, PM2, PP3, PP4 (Richards 2015).

GBA1: PM3:Strong, PS1, PM2, PS3:Supporting