ClinVar Genomic variation as it relates to human health

Variant summary: GBA c.680A>G (p.Asn227Ser) results in a conservative amino acid change located in the Glycosyl hydrolase family 30, TIM-barrel domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251308 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GBA causing Gaucher Disease (7.2e-05 vs 0.005), allowing no conclusion about variant significance. The variant has been reported in the homozygous and compound heterozygous genotypes in numerous publications of patients with Gaucher Disease and has also been reported in patients in cis with a second variant E326K (example, Alfonso_2007, Biegstraaten_2011, Erdos_2007, Jeong_2011, Tajima_2010). The variant has been shown to result in moderate reductions in enzyme activity via various expression systems (~25%-66% residual activity; Malini_2014, Tajima_2010, Montfort_2004). While the E326K variant does not have a significant effect on enzyme activity in these studies (and has not been observed in GD patients on its own), the addition of the variant of interest resulted in greater effects on activity (completely inactive in one study, 25% residual activity in a second study). Despite the high residual activity reported in these studies, patients with a rare myoclonic epilepsy phenoptype have also been reported in association with the variant (Kowarz_2005). Additionally, in a pair of monozygotic twins, both homozygous for the variant and both having <20% glucocerebrosidase activity in leukocytes, highly discordant manifestations of Gaucher disease were observed: one sister had severe visceral involvment, epilepsy and cerebellar syndrome, while the other had no symptoms of Gaucher disease (Biegstraaten_2011). This report indicates incomplete penetrance and/or variable expressivity, even in individuals having near identical genetic sequence. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One of these submitters cites overlapping evidences utilized in the context of this evaluation. Both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was re-classified as pathogenic mindful of the caveats of penetrance and expressivity summarized above.

The p.Asn227Ser variant in GBA has been reported in at least 28 individuals with Gaucher disease, segregated with disease in 4 affected relatives from 2 families (PMID: 20004867, 12595585, 8829654, 20729108, 17395504, 30497978, 27872820, 24022302, 30382391, 15146461, 16086325, 21056933), has been identified in 0.020% (5/24920) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs364897). 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 pathogenic by EGL Genetic Diagnostics and OMIM, and likely pathogenic by Integrated Genetics in ClinVar (Variation ID: 4314). Twins that are monozygous and homozygous for this variant show different clinical presentations, suggesting that there may be incomplete penetrance or variable expressivity associated with this variant. In vitro functional studies provide some evidence that the p.Asn227Ser variant may slightly impact protein function either alone or in cis with another pathogenic variant (PMID: 20004867, 26743617, 27865684, 30497978, 15146461, 24022302). However, these types of assays may not accurately represent biological function. The presence of this variant in 3 affected homozygotes and in combination with at least 7 reported pathogenic variants and in 14 individuals with Gaucher disease increases the likelihood that the p.Asn227Ser variant is pathogenic (PMID: 8829654, 21056933, 12595585, 8829654, 20729108, 30497978, 27872820, 16086325; VariationID: 4302, 4288, 93459, 4290, 99352, 76478, 4297). The phenotype of individuals homozygous and heterozygous for this variant is highly specific for Gaucher disease based on low glucocerebrosidase activity consistent with Gaucher disease (PMID: 30382391, 16086325, 21056933). In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner with incomplete penetrance or variable expressivity based on multiple occurrences with pathogenic GBA variants in individuals with Gaucher Disease. ACMG/AMP Criteria applied: PM3_very-strong, PM5, PM2_supporting, PS3_supporting, PP4, PP1 (Richards 2015).

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 227 of the GBA protein (p.Asn227Ser). This variant is present in population databases (rs364897, gnomAD 0.02%). This missense change has been observed in individuals with Gaucher disease and/or Parkinson's disease (PMID: 8829654, 21056933, 22387070, 26709268). This variant is also known as p.Asn188Ser or N188S. ClinVar contains an entry for this variant (Variation ID: 4314). 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) performed at Invitae indicates that this missense variant is not expected to disrupt GBA protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GBA function (PMID: 15146461, 20004867, 24022302). For these reasons, this variant has been classified as Pathogenic.

GBA1: PM3:Very Strong, PM2, PM5, PS3:Supporting