ClinVar Miner

Submissions for variant NM_000157.4(GBA):c.1296G>A (p.Trp432Ter) (rs1484043383)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000585394 SCV000692644 uncertain significance not provided 2017-07-01 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV001249088 SCV001423054 likely pathogenic Gaucher disease 2020-01-22 no assertion criteria provided curation The p.Trp432Ter variant in GBA has been reported in the heterozygous state in one Japanese patient with Parkinson disease (PMID: 24126159), and has been identified in 0.001% (1/113738) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1484043383). 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: 493049) as a VUS by Praxis fuer Humangenetik Tuebingen without indicating zygosity or phenotype. This nonsense variant leads to a premature termination codon at position 432, which is predicted to lead to a truncated or absent protein. Loss of function of the GBA gene is an established disease mechanism in autosomal recessive Gaucher disease. However, this variant has never been reported in the literature in an individual with Gaucher disease. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PVS1 (Richards 2015).

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