ClinVar Genomic variation as it relates to human health

PP4, PM1, PM2, PM5

This variant, c.680_681delinsGG, is a complex sequence change that results in the deletion of 1 and insertion of 1 amino acid(s) in the GBA protein (p.Asn227Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with Gaucher disease (PMID: 29934114). ClinVar contains an entry for this variant (Variation ID: 167132). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). This variant disrupts the p.Asn227 amino acid residue in GBA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8829654, 21056933, 22387070, 26709268). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Variant summary: GBA1 c.680_681delinsGG (p.Asn227Arg) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, TIM-barrel domain (IPR033453) of the encoded protein sequence. One of two in-silico tools predict a benign effect of the variant on protein function while multiple in-silico tools are "not available". The variant was absent in 282624 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.680_681delinsGG has been reported in the literature as a presumably compound heterozygous genotype (phase not clearly specified) in at-least one individual affected with type 2 Gaucher disease (example, Kang_2018). It has also been reported with other variants in the GBA among individuals with unspecified phase information. These data do not allow any conclusion about variant significance. A different variant affecting the same codon has been classified as pathogenic by our lab (c.680A>G, p.Asn227Ser), supporting the critical relevance of codon 227 to GBA1 protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19433657, 34134921, 33606887, 29934114, 23588557). ClinVar contains an entry for this variant (Variation ID: 167132). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.