Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000144063 | SCV000800261 | uncertain significance | Biotinidase deficiency | 2018-05-29 | criteria provided, single submitter | clinical testing | |
| Mendelics | RCV000144063 | SCV001136338 | likely pathogenic | Biotinidase deficiency | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000144063 | SCV002151883 | pathogenic | Biotinidase deficiency | 2024-01-22 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 2 of the BTD gene. It does not directly change the encoded amino acid sequence of the BTD protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs587783008, gnomAD 0.01%). This variant has been observed in individual(s) with biotinidase deficiency (PMID: 24797656, 26810761, 30912303). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 156006). Studies have shown that this variant alters BTD gene expression (PMID: 24797656). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000144063 | SCV003929215 | likely pathogenic | Biotinidase deficiency | 2023-04-13 | criteria provided, single submitter | clinical testing | 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. |
| Baylor Genetics | RCV000144063 | SCV004211458 | likely pathogenic | Biotinidase deficiency | 2023-05-25 | criteria provided, single submitter | clinical testing | |
| Molecular Genetics Diagnostic Laboratory, |
RCV000144063 | SCV000189136 | pathogenic | Biotinidase deficiency | no assertion criteria provided | clinical testing |