ClinVar Genomic variation as it relates to human health

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: 12204005, 22429443, 32822875, 32547927, 22964618, 29934114, 11259172, 24022302, 10744424, 29091352, 22247978, 23430543, 8790604). This variant segregates with disease in multiple families (PMID: 29091352, 29934114, 9153297). The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). Assessment of experimental evidence is inconclusive and computational tools yielded discordant predictions regarding the effect of this variant on protein function (PMID: 11259172, 25084554).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.

Criteria applied: PM3_VSTR,PS3_MOD,PM2_SUP,PP3

Variant summary: The GBA c.721G>A (p.Gly241Arg) variant (alternatively also known as G202R) involves the alteration of a conserved nucleotide, is located in TIM-barrel domain of the protein (InterPro) and 2/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 3/121276 control chromosomes from ExAC at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). This variant has been found in several patients with GD mainly from Europe in compound heterozygous state with other known pathogenic variants as well as in homozygous state, including an evidence of cosegregation with disease. In an Italian study, this variant was the third most common pathogenic variant (Filocamo_2002). In vitro functional studies show that this variant leads to severely compromised enzymatic activity and/or trafficking (Grace_1997, Torralba_2001, review by Yu_2009). The functional outcome coupled with severe phenotype (type 2 GD) in patients carrying this variant in homozygous state indicates that it could be a severe mutation. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

The p.Gly241Arg variant in GBA has been reported in at least 13 individuals with Gaucher disease (PMID: 22429443, 24022302, 11259172) and has been identified in 0.012% (2/16254) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs409652). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Trio analysis showed this variant to be de novo in one individual (PMID: 24022302). In vitro functional studies demonstrating reduced enzyme activity in transfected COS-7 cells provide some evidence that the p.Gly241Arg variant may impact protein function (PMID: 11259172, 25084554). However, these types of assays may not accurately represent biological function. Computational prediction tools suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The Gly at position 241 is highly conserved in mammals and evolutionary distant species, but 1 mammal (Gorilla) carries an Arg, raising the possibility that this change at this position may be tolerated. The presence of this variant in combination with reported pathogenic variants in 12 individuals with Gaucher disease increases the likelihood that the p.Gly241Arg variant is pathogenic (VariationID: 4288, 4290; PMID: 22429443, 11259172). 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, functional studies, and the occurrence of the variant de novo in a Gaucher disease patient. ACMG/AMP Criteria applied: PM3_very-strong, PS3, PS2, PM2_supporting (Richards 2015).

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 241 of the GBA protein (p.Gly241Arg). 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 missense change has been observed in individual(s) with Gaucher disease and/or Parkinson's disease (PMID: 12204005, 22173904, 22247978, 23430543, 26117366, 29091352). This variant is also known as p.Gly202Arg or G202R. ClinVar contains an entry for this variant (Variation ID: 93459). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GBA protein function. Experimental studies have shown that this missense change affects GBA function (PMID: 9153297). This variant disrupts the p.Gly241 amino acid residue in GBA. Other variant(s) that disrupt this residue have been observed in individuals with GBA-related conditions (PMID: 10744424), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 26792850); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(G202R); This variant is associated with the following publications: (PMID: 28727984, 27789132, 11783951, 25188399, 27816428, 27836528, 24022302, 22173904, 18078074, 29091352, 34779914, 34820281, 33301762, 34867278, 19830760, 22247978, 26792850, 27872820, 12204005, 23430543, 9516376, 22623374, 22964618, 17427031, 11259172, 8790604, 30461613, 31996268, 34426522, 31589614, 32677286, 32618053, 32658388, 34308104, 22429443, 33176831, 29934114, 26117366, 37432431, 37198191, 35861376, 36097244)

GBA1: PM3:Very Strong, PM2, PM5