ClinVar Miner

Submissions for variant NM_000157.4(GBA):c.535G>C (p.Asp179His) (rs147138516)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000487788 SCV000574791 uncertain significance not provided 2016-12-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586576 SCV000697587 likely pathogenic Gaucher disease 2020-10-02 criteria provided, single submitter clinical testing Variant summary: GBA c.535G>C (p.Asp179His) results in a non-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 0.00013 in 255930 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in GBA causing Gaucher Disease (0.00013 vs 0.005), allowing no conclusion about variant significance. The variant was reported in the literature in a haplotype with c.1093G>A (p.Glu365Lys) in two brothers diagnosed with Type I Gaucher disease (GD) as well as in one unrelated GD patient (Eyal_1991, Park_2003). These data indicate that the variant may be associated with Gaucher Disease. In functional studies, the c.535G>C variant alone was shown to result in a mild reduction of enzyme activity (approximately 50-74% residual acitivty), while the presence of the complex allele c.535G>C + c.1093G>A resulted in significantly decreased activity compared to either individual allele (20-25% residual activity; Grace_1999, Ron_2005). The c.535G>C variant and c.535G>C + c.1093G>A complex allele have also been reported in patients with Parkinson's Disease (PD) and dementia, and it has been suggested that monoallelic variants in GBA may be risk factors for PD, but these associations have not been conclusively determined (e.g. Lesage_2011, Meeus_2012, Tsuang_2012, Nalls_2013, Crosiers_2016, Liu_2016, Mata_2016, Blauwendraat_2017, Moors_2019, Geut_2019). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000586576 SCV001422955 uncertain significance Gaucher disease 2020-01-14 no assertion criteria provided curation The p.Asp179His variant in GBA has been reported in at least 3 individuals with Gaucher disease (PMID: 22350617, 22623374, 10079102) and has been identified in 0.027% (35/128762) of European (non-Finnish) chromosomes, including 1 homozygote, by the Genome Aggregation Database (gnomAD,; dbSNP rs147138516). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (VariationID: 242811) as likely pathogenic by Integrated Genetics and as a VUS by Praxis fuer Humangenetik Tuebingen. In vitro functional studies provide some evidence that the p.Asp179His variant may not impact protein function (PMID: 21831682, 10079102). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in combination with a reported pathogenic variant and in an individual with Gaucher disease increases the likelihood that the p.Asp179His variant is pathogenic (VariationID: 4297; PMID: 22350617). In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: BS3_supporting, PM3_supporting (Richards 2015).

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