Description
Variant summary: BTD c.-17_-17+3delGGTA is located at the splice-site region in the non-coding exon 1, upstream of the initiation codon, and is predicted to abolish the canonical 5' splice donor site (Alamut). These predictions have yet to be confirmed by functional studies. The variant was absent in 249988 control chromosomes (gnomAD). To our knowledge, no occurrence of c.-17_-17+3delGGTA in individuals affected with Biotinidase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. While exon 1 is absent in most tissues in the GTEx database, and is a non-coding exon in the transcript utalized for this classification, there is evidence that exon 1 remains an important region of the gene. Another variant which impacts the same splice-site, c.-17+1G>A, has been reported a patient with partial Biotinidase Deficiency (Murry_2018) and is reported via ClinVar as likely pathogenic. Additionally, a 107-kb contiguous deletion of three genes in homozygosity, including exon 1 of the BTD gene, has been reported in a child whose symptoms were apparently solely attributable to the BTD gene and improved with biotin supplementation (Senanayake_2015). The authors of this study concluded that deletion of exon 1 results in the inability to synthesize the active enzyme product, as exon 1 contains the initiation site and leader signal sequence of the enzyme, supporting a critical role for this exon, with the caveat that a deletion of the region may have a different impact than a variant affecting splicing (Senanayake et al. 2015). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
