ClinVar Genomic variation as it relates to human health

NM_001005741.2(GBA):c.84dupG(L29Afs*18, aka p.L29Afs*18) is classified as pathogenic in the context of Gaucher disease and may be associated with Type 1, 2 or 3. Sources cited for classification include the following: PMID 21742527, 8487270, 1961718, 1348297 and 8432537. Classification of NM_001005741.2(GBA):c.84dupG(L29Afs*18, aka p.L29Afs*18) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.‚Äã

The p.Leu29AlafsTer18 variant in GBA has been reported in at least 70 individuals with Gaucher disease (PMID: 10777718, 19513999) and has been identified in 0.077% (8/10370) of Ashkenazi Jewish chromosomes, 0.006% (2/35440) of Latino chromosomes, and 0.002% (2/128886) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs387906315). 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: 4302) as pathogenic by EGL Genetic Diagnostics, Counsyl, Integrated Genetics, and OMIM. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 29 and leads to a premature termination codon 18 amino acids downstream. This alteration is then 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. The presence of this variant in combination with a reported pathogenic variant and in 70 individuals with Gaucher disease increases the likelihood that the p.Leu29AlafsTer18 variant is pathogenic (VariationID: 4290; PMID: 10777718, 19513999). In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on the prediction that it causes loss of function and the presence of the variant in combination with a known pathogenic variant. ACMG/AMP Criteria applied: PVS1, PM3_very-strong, PM2_supporting (Richards 2015).

Identified in the heterozygous state in patients with Parkinson disease, but also in control individuals (Ruskey et al., 2019; Gan-Or et al., 2015; Choi et al., 2011); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 10796875, 21228398, 25653295, 26096741, 22975760, 27717005, 25946768, 21700325, 29842932, 8889578, 7789963, 8516282, 34017912, 29471591, 17875915, 21742527, 1961718)

This sequence change creates a premature translational stop signal (p.Leu29Alafs*18) in the GBA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GBA are known to be pathogenic (PMID: 9153297, 10079102, 10796875, 11783951). This variant is present in population databases (rs387906315, gnomAD 0.09%). This premature translational stop signal has been observed in individuals with Gaucher disease and/or Parkinson's disease and dementia with Lewy bodies (PMID: 1961718, 21742527, 25653295, 25933391, 26096741, 27717005). This variant is also known as 84GG. ClinVar contains an entry for this variant (Variation ID: 4302). For these reasons, this variant has been classified as Pathogenic.

Variant summary: The GBA c.84dupG (p.Leu29Alafs) variant results in a premature termination codon, predicted to cause a truncated or absent GBA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory and other labs/reputable databases in ClinVar (e.g. c.487delG, c.1029delT, c.1265_1319del55, etc.). This variant was found in 6/121380 control chromosomes from ExAC at a frequency of 0.0000494, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). This variant is reported as one of the common pathogenic variants in literature found especially in Ashkenazi Jews population (Beutler_1991, Koprivica_2000, Brautbar_2003, Giraldo_2011). Functional data are consistent with predicted outcome of this variant because no translation product could be detected in an in vitro translation system and little or no enzyme antigen attributed to this allele could be found in cell lines from patients (Beutler_1991). Three clinical labs (via ClinVar) and a reputable database have classified this variant as pathogenic. Taken together, this variant has been classified as a pathogenic.

The GBA1 c.84dupG variant is predicted to result in a frameshift and premature protein termination (p.Leu29Alafs*18). This variant is known to be causative for autosomal recessive Gaucher disease (Beutler et al. 1991. PubMed ID: 1961718). This variant is reported in 0.077% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/4302/). Given the evidence, we interpret this variant as pathogenic.