ClinVar Miner

Submissions for variant NM_000157.4(GBA):c.680A>G (p.Asn227Ser) (rs364897)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000723402 SCV000111222 pathogenic not provided 2017-02-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000020156 SCV000697592 likely pathogenic Gaucher disease 2017-06-02 criteria provided, single submitter clinical testing Variant summary: The GBA c.680A>G (p.Asn227Ser) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 8/117424 control chromosomes at a frequency of 0.0000681, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). The variant has been reported in numerous publications in Gaucher Disease patients in the homozygous and compound heterozygous state, and also has been reported in patients in cis with a second variant E326K. 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 rare myoclonic 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 in leukocytes, highly discordant manifestations of Gaucher disease were observed with one sister having 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. Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic, without evidence for independent evaluation. Taken together, this variant is classified as likely pathogenic, noting the incomplete penetrance/variable expressivity, and the fact that this variant may have a modifying role in disease.
Invitae RCV000723402 SCV000960920 pathogenic not provided 2020-07-26 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 227 of the GBA protein (p.Asn227Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. The frequency data for this variant in the population databases (rs364897, ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has been observed in several individuals affected with Gaucher disease (PMID: 26709268, 8829654, 21056933) and Parkinson's disease (PMID: 22387070). ClinVar contains an entry for this variant (Variation ID: 4314). This variant is also known as p.Asn188Ser or N188S in the literature. Experimental studies have shown that this missense change disrupt GBA enzyme activity (PMID: 24022302, 15146461, 20004867). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001004131 SCV001162862 pathogenic Gaucher disease type I; Gaucher disease type II; Gaucher disease type III; Gaucher disease type 3C criteria provided, single submitter clinical testing
OMIM RCV000004557 SCV000024731 pathogenic Gaucher disease type I 2004-06-01 no assertion criteria provided literature only
OMIM RCV000004558 SCV000024732 pathogenic Gaucher disease type III 2004-06-01 no assertion criteria provided literature only
GeneReviews RCV000020156 SCV000040483 pathologic Gaucher disease 2011-02-01 no assertion criteria provided curation Converted during submission to Pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000020156 SCV001422959 pathogenic Gaucher disease 2020-01-14 no assertion criteria provided curation 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).

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