Description
Variant summary: BTD c.250-15delT, also referred to as c.310-15delT, alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predicts the variant creates a 3' acceptor site, two predict the variant weakens a canonical 3' acceptor site, and one predicts the variant has no significant impact on splicing. However, a functional study found no evidence that the variant impacts splicing (Li_2014). The variant allele was found at a frequency of 8.3e-06 in 241528 control chromosomes (gnomAD). c.250-15delT has been reported in the literature in the compound heterozygous state in individuals affected with partial Biotinidase Deficiency, including at least one case where it was confirmed to be in trans with a pathogenic variant (e.g. Li_2014, Procter_2016, Carvalho_2019, Carvalho_2020). These data indicate that the variant may be associated with disease. Experimental evidence evaluating an impact of the variant found that although it does not appear to impact splicing, the variant may result in decreased mRNA expression (Li_2014). This study found that a patient who was compound heterozygous for the variant and the patient's mother, who was a heterozygous carrier, both exhibited decreased mRNA expression, approximately 40% and 65%, respectively, compared to control individuals. Three ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance, likely pathogenic and 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 |
