ClinVar Genomic variation as it relates to human health

The p.[L483P;A495P;V499V] pathogenic mutation (also known as c.[1448T>C;1483G>C;1497G>C]), located in coding exon 10 of the GBA gene, results from a T to C substitution at nucleotide position 1448, a G to C substitution at nucleotide position 1483, and a G to C substitution at nucleotide position 1497. This complex allele, also referred to as recNciI and L444P;A456P;V460V, has been reported in multiple cases of Gaucher disease, either in homozygous state or in trans with another GBA pathogenic mutation. It has been suggested that the complex allele results from gene recombination between GBA and its pseudogene (Zimran A et al. J. Clin. Invest., 1990 Jan;85:219-22; Latham T et al. Am. J. Hum. Genet., 1990 Jul;47:79-86; Horowitz M et al. Am. J. Hum. Genet., 1993 Oct;53:921-30; Strasberg PM et al. Biochem. Med. Metab. Biol., 1994 Oct;53:16-21; Sidransky E et al. J. Med. Genet., 1996 Feb;33:132-6; Tayebi N et al. Am. J. Hum. Genet., 2003 Mar;72:519-34; Saranjam H et al. Eur. J. Hum. Genet., 2013 Jan;21:115-7). In addition, functional studies showed that the complex allele greatly reduces enzyme activity (Grace ME et al. J. Biol. Chem., 1994 Jan;269:2283-91; Pasmanik-Chor M et al. Hum. Mol. Genet., 1997 Jun;6:887-95). Based on the supporting evidence, this complex allele is interpreted as a disease-causing mutation.

GBA1: PM2, PM3, PP1, PP4

Variant summary: GBA1 c.1483G>C (p.Ala495Pro) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, beta sandwich domain (IPR033452) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00058 in 1612176 control chromosomes, predominantly at a frequency of 0.0017 within the Latino subpopulation in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in GBA1 causing Gaucher Disease (0.00058 vs 0.005), allowing no conclusion about variant significance. c.1483G>C has been reported in the literature as part of the frequently encountered GBA complex alleles, RecTL or Rec NciI in individuals affected with Gaucher Disease and GBA-associated phenotypes of Parkinson Disease (example, Latham_1990, Grace_1994, Zimran_1994, Lau_1999, Stone_2000, Wittman_2012, Jesus_2016, Bhutada_2018, Kang_2018, Marchi_2020, Petrucci_2020). Rec TL and Rec NCiI are complex recombination alleles that carry two or more disease causing mutations due to gene conversion events between the GBA and the pseudo-GBA (GBAP) genes. To our knowledge, this variant has never been reported in isolation as a homozygous or compound heterozygous genotype in individuals with Gaugher Disease. These report(s) do not provide unequivocal conclusions about association of the variant with Gaucher Disease. At least one publication reports in-vitro experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Grace_1994). The following publications have been ascertained in the context of this evaluation (PMID: 29854527, 8294487, 28030538, 29934114, 2349952, 10369158, 32031266, 32658388, 38647370, 10685993, 23430949, 8160756). ClinVar contains an entry for this variant (Variation ID: 93450). Based on the evidence outlined above, the variant was classified as uncertain significance.