Submissions for variant NM_020944.3(GBA2):c.2202del (p.Tyr735fs)

gnomAD frequency: 0.00001  dbSNP: rs1448182827

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000687537	SCV000815109	pathogenic	Spastic paraplegia	2022-04-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr735Ilefs*26) in the GBA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GBA2 are known to be pathogenic (PMID: 23332916, 23332917). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 567447). This variant has not been reported in the literature in individuals affected with GBA2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.002%).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526754	SCV005039771	pathogenic	Hereditary spastic paraplegia 46	2024-03-19	criteria provided, single submitter	clinical testing	Variant summary: GBA2 c.2202delC (p.Tyr735IlefsX26) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 8e-06 in 251426 control chromosomes (gnomAD). c.2202delC has been reported in the literature in the homozygous state in at least two individuals affected with Spastic Paraplegia 46, Autosomal Recessive (Haj Salem_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33397523). ClinVar contains an entry for this variant (Variation ID: 567447). Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004758048	SCV005347735	likely pathogenic	GBA2-related disorder	2024-05-06	no assertion criteria provided	clinical testing	The GBA2 c.2202delC variant is predicted to result in a frameshift and premature protein termination (p.Tyr735Ilefs*26). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in GBA2 are expected to be pathogenic. This variant is interpreted as likely pathogenic.