ClinVar

Description

Variant summary: The GBA c.1297G>T (p.Val433Leu) variant (alternatively also known as V394L) involves the alteration of a conserved nucleotide, is located in TIM-barrel domain of the protein (InterPro) and is predicted to be damaging by 2/4 in silico tools (SNPsandGO not captured due to low reliability index). This variant was found in 4/120330 control chromosomes from ExAC at a frequency of 0.0000332, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). The variant is one of the common pathogenic variants in Ashkenazi population (Beutler_1993, Elstein_2005, and Orenstein_2014). In a genotype-phenotype study (Elstein_2005) that included N370S/V394L compound heterozygotes, most of the patients had mild disease; only 8 patients required specific enzyme therapy, none was splenectomized. Only 3 patients had skeletal involvement, but other baseline parameters were very diverse. Authors note that although genotype-phenotype correlation in this case may be difficult, because the V394L mutation when seen in a compound heterozygote with a null allele results in neuronopathic disease, one cannot conclude that this mutation is protective of neuronopathic disease. Patients carrying this variant in homozygous state have not been reported so far. Functional studies in insect cell system and mouse models have shown that the variant leads to severe decrease in enzymatic activity (11-15 % of wildtype activity) and neurological phenotype is recapitulated in transgenic mice carrying this variant (Grace_1994, Liou_2006, Xu_2011). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.