ClinVar Genomic variation as it relates to human health

Identified in the heterozygous state in patients with Parkinson disease (Neumann et al., 2009; Choi et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Previously reported as R257Q due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 33176831, 27312774, 12791040, 21704274, 10796875, 19286695, 17395504, 21384230, 22772462, 10685993, 8790604, 22387070, 26709268, 29091352, 28506293, 30764785, 27717005)

The GBA c.887G>A; p.Arg296Gln variant (rs78973108), also known as Arg257Gln, is reported in the literature in the homozygous and compound heterozygous state in multiple individuals and families affected with Gaucher syndrome (Beutler 1994, Erdos 2007, Kim 2020, Lee 2012, Stone 2000). Functional analyses of the variant protein show a dramatic reduction in GBA enzyme activity (Kim 2020). This variant is also reported in ClinVar (Variation ID: 4328). This variant is found in the general population with an overall allele frequency of 0.004% (10/282590 alleles) in the Genome Aggregation Database. The arginine at codon 296 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.942). Based on available information, this variant is considered to be pathogenic. References: Beutler E et al. Glucocerebrosidase mutations in Gaucher disease. Mol Med. 1994 Nov;1(1):82-92. PMID: 8790604. Erdos M et al. Genetic and clinical features of patients with Gaucher disease in Hungary. Blood Cells Mol Dis. 2007 Jul-Aug;39(1):119-23. PMID: 17395504. Kim YM et al. The GBA p.G85E mutation in Korean patients with non-neuronopathic Gaucher disease: founder and neuroprotective effects. Orphanet J Rare Dis. 2020 Nov 11;15(1):318. PMID: 33176831. Lee JY et al. Clinical and genetic characteristics of Gaucher disease according to phenotypic subgroups. Korean J Pediatr. 2012 Feb;55(2):48-53. PMID: 22375149. Stone DL et al. Type 2 Gaucher disease: the collodion baby phenotype revisited. Arch Dis Child Fetal Neonatal Ed. 2000 Mar;82(2):F163-6. PMID: 10685993.

The p.Arg296Gln variant in GBA has been reported in at least 15 individuals with Gaucher disease (PMID: 17395504, 20729108, 21384230, 25435509, 29091352, 30764785, 21704274) and has been identified in 0.008% (2/24970) of African chromosomes and 0.006% (8/128908) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs78973108). 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: 4328) as Pathogenic by EGL Genetic Diagnostics, GeneDx, Fulgent Genetics, OMIM, and Integrated Genetics. In vitro functional studies demonstrating nearly undetectable levels of beta-glucosidase in patient fibroblasts provide some evidence that the p.Arg296Gln variant may impact protein function (PMID: 29091352). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in one affected homozygote and in combination with reported pathogenic variants in 11 individuals with Gaucher disease increases the likelihood that the p.Arg296Gln variant is pathogenic (VariationID: 4290, 4321, 4296, 93459, 4301, 4288 PMID: 17395504, 20729108, 21384230, 25435509, 29091352). 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 in many individuals, in vitro functional studies, and computational evidence. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PS3_moderate, PP3 (Richards 2015).

The GBA c.887G>A (p.Arg296Gln) missense variant, also referred to as p.Arg257Gln, has been identified in individuals with Gaucher disease. In the majority of affected indivduals, the variant was found in a compound heterozygous state with a second missense variant. In one individual it was found in a compound heterozygous state with a 55 bp deletion and in another in a homozygous state (PMID: 17395504; PMID: 20729108; PMID: 25435509). This variant is reported in the Genome Aggregation Database in eight alleles at a frequency of 0.000062 in the European (non-Finnish) population (version 2.1.1). Functional evidence demonstrated that this variant impacts protein function (PMID: 29091352). Multiple lines of computational evidence suggest the variant may impact the gene or gene product. Based on the available evidence, the c.887G>A (p.Arg296Gln) variant is classified as pathogenic for Gaucher disease.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Gaucher disease (MIM# 230800, 230900, 231000, 231005, 608013). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Gaucher disease is associated with marked clinical variability, even within the same family (PMID: 31010158). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated glycosyl hydrolase family 30 TIM-barrel domain (NCBI). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported in multiple individuals with Gaucher disease (ClinVar, PMID: 33176831). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Variant summary: GBA c.887G>A (p.Arg296Gln) results in a conservative amino acid change located in the glycosyl hydrolase family 30, TIM-barrel domain (IPR033453) of the encoded protein sequence. 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 3.2e-05 in 276952 control chromosomes (gnomAD). c.887G>A has been reported in the literature in multiple individuals affected with Gaucher Disease (Alfonso 2007, Erdos 2007, Lee 2012, Lopez 2016). 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 (Lee 2012). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic (PMID: 33176831, 17395504, 21384230, 28506293, 20729108, 21704274, 32822875, 8790604, 32547927, 30764785, 10685993, 25435509). This variant segregates with disease with disease in multiple families (PMID: 8301495, 29091352). The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). Computational tools yielded predictions that this amino acid change may be damaging to the protein.This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.

PS3, PM3_Strong, PP3