ClinVar Genomic variation as it relates to human health

Variant summary: GLB1 c.75+2dupT is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5 prime splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing. The variant allele was found at a frequency of 0.00021 in 271704 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GLB1 causing GM1 gangliosidosis (0.00021 vs 0.002), allowing no conclusion about variant significance. c.75+2dupT has been reported in the literature in multiple individuals affected with GM1 gangliosidosis. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0209 - Splice variant (canonical or non-canonical) proven to affect splicing/expression of the transcript with uncertain effect on protein structure (intron 1 of 15). Functional studies have proven this variant results in two new mRNA transcripts; a frameshift which is predicted to undergo nonsense mediated decay (PMID: 8198123), and the inframe skipping of exon 2 (PMID: 8199591). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (58 heterozygotes, 0 homozygotes). (P) 0505 - Abnormal splicing is predicted by in silico tools. (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in multiple patients with GM1 gangliosidosis. Homozygous patients, or those in compound heterozygous with a truncating variant, had severe, infantile onset disease. A patient in compound heterozygous with a missense variant had a milder form of disease (ClinVar, PMID: 8198123, PMID: 8199591, PMID: 21497194). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

Variant results in activation of a cryptic splice donor site and insertion of 20 base pairs of intronic sequence, resulting in a frameshift and protein truncation (Chakraborty et al., 1994; Morrone et al., 1994); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 8199591, 33737400, 21497194, 29352662, 30408610, 25936995, 29160035, 28476546, 31761138, 33942996, 33240792, 33558080, 8198123)

The splice site c.75+2dup variant in the GLB1 gene has been reported in a compound heterozygous state in an individual affected with GM1 gangliosidosis (Myers KA. et al., 2018). Experimental studies have shown that this variant disrupts mRNA splicing (Morrone A. et al., 1994). This variant is reported with the allele frequency (0.02%) in the gnomAD and is novel (not in any individuals) in 1000 genome database. It has been submitted to ClinVar as a Pathogenic variant. This variant affects the invariant GT donor splice site. This nucleotide change in GLB1 is predicted to be conserved across species. For these reasons, this variant has been classified as Pathogenic.

This sequence change falls in intron 1 of the GLB1 gene. It does not directly change the encoded amino acid sequence of the GLB1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs766823411, gnomAD 0.1%). This variant has been observed in individuals with GM1 gangliosidosis (PMID: 8198123, 8199591, 29160035). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 936). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in retention of 20bp of intron1 and introduces a premature termination codon (PMID: 8198123, 8199591). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.