ClinVar Genomic variation as it relates to human health

Variant summary: GBA c.1505G>A (p.Arg502His) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, beta sandwich domain (IPR033452) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Three predict the variant weakens a 5' donor site. Two predict the variant creates a 3' acceptor site. At least one publication reports that this mutation resulted in altered splicing. The authors report that in the mutant allele, the normal 5'splicing site was not recognized and instead the next in intron 10 was used as splicing donor site. This resulted in a 12bp insertion in the mRNA downstream from codon 463 resulting in a new stop codon (Ohshima_1993). The variant allele was found at a frequency of 8e-06 in 251168 control chromosomes (gnomAD) and has been reported in the literature in multiple individuals (both homozygous and compound heterozygous) affected with Gaucher Disease ((Haverkaemper_2011, Alfonso_2007, Shehi_2011, Ohshima_1993, Moraitou_2001). These data indicate that the variant is very likely to be associated with disease. At least one publication reports reduced enzymatic activity in a homozygous patient (Haverkaemper_2011). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

NM_001005741.2(GBA):c.1505G>A(R502H, aka R463H) is classified as likely pathogenic in the context of Gaucher disease. Sources cited for classification include the following: PMID 23056756, 24278166, 22429443, 17427031, 21823541, and 21455010. Classification of NM_001005741.2(GBA):c.1505G>A(R502H, aka R463H) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses and is very rare or not present in genetic databases of healthy individuals. Please note: this variant was assessed in the context of healthy population screening.

The p.Arg502His variant in GBA has been reported in at least 8 individuals with Gaucher disease (PMID: 23332636, 17427031, 28727984, 25435509; doi:10.4172/2167-0889.1000122) and has been identified in 0.003% (1/34592) of Latino chromosomes and 0.001% (1/113456) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs80356772). 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: 21070) as likely pathogenic by Counsyl. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant is located in the last base of the exon, which is part of the 5' splice region. Additional computational tools do suggest an impact to splicing. However, 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.Arg502Cys, has been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (VariationID: 4295). Additionally, the presence of this variant in combination with reported pathogenic variants and in 6 individuals with Gaucher disease increases the likelihood that the p.Arg502His variant is pathogenic (VariationID: 4290, 4288; PMID: 23332636, 17427031, 28727984, doi:10.4172/2167-0889.1000122). The phenotype of an individual compound heterozygous for this variant is highly specific for Gaucher disease based on glucocerebrosidase activity being <10% of normal, consistent with disease (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 presence of another pathogenic variant at the same location, and the presence of the variant in an individual with a phenotype specific to the disease. ACMG/AMP Criteria applied: PM3_strong, PM2, PM5, PP3, PP4 (Richards 2015).

This sequence change affects codon 502 of the GBA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GBA protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has been observed in individuals with dementia with Lewy bodies, Gaucher disease, and/or Parkinson's disease (PMID: 7694727, 17427031, 21455010, 22812582, 23588557, 24313877, 29140481). This variant is also known as IVS10-1G>A, p.Arg463His, or R463H. ClinVar contains an entry for this variant (Variation ID: 21070). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in inclusion of 12 base pairs from intron 11 (also known as intron 10) and introduces a new termination codon (PMID: 7694727). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

GBA1: PM3:Strong, PS3, PM2, PP4:Moderate