ClinVar Miner

Submissions for variant NM_020944.3(GBA2):c.515G>A (p.Arg172His)

gnomAD frequency: 0.00002  dbSNP: rs200268523
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV000999165 SCV001155645 uncertain significance not provided 2019-04-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV001815017 SCV002061935 uncertain significance not specified 2021-06-17 criteria provided, single submitter clinical testing DNA sequence analysis of the GBA2 gene demonstrated a homozygous sequence change, c.515G>A, in exon 3 that results in an amino acid change, p.Arg172His. This sequence change has been described in one African/African American and one Finnish European individuals in the gnomAD population database (dbSNP rs200268523). This sequence change has been previously described in the compound heterozygous state in a family with hereditary spastic paraparesis (PMID: 32590105). The p.Arg172His change affects a moderately conserved amino acid residue located in the N-terminal glycosyl hydrolase domain of the glucosylceramidase beta 2 (GBA2) protein. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg172His substitution. Due to the lack of convincing functional studies, the clinical significance of the p.Arg172His change remains unknown at this time.
Labcorp Genetics (formerly Invitae), Labcorp RCV002549119 SCV003522253 pathogenic Spastic paraplegia 2022-09-27 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg172 amino acid residue in GBA2. Other variant(s) that disrupt this residue have been observed in individuals with GBA2-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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 GBA2 protein function. ClinVar contains an entry for this variant (Variation ID: 810379). This missense change has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: 32590105; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs200268523, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 172 of the GBA2 protein (p.Arg172His).

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.