ClinVar Miner

Submissions for variant NM_001370658.1(BTD):c.-17+2T>C

gnomAD frequency: 0.00001  dbSNP: rs745648160
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001379913 SCV001577813 likely pathogenic Biotinidase deficiency 2025-01-06 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 1 of the BTD gene. However, it is currently unclear if variants that occur in this region of the gene cause disease. This variant is present in population databases (rs745648160, gnomAD 0.03%). Disruption of this splice site has been observed in individual(s) with biotinidase deficiency (PMID: 29728376, 38299772). 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: 1068379). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001379913 SCV002511630 likely pathogenic Biotinidase deficiency 2022-04-05 criteria provided, single submitter clinical testing Variant summary: BTD c.-17+2T>C is located in a splice-site region of the non-coding exon 1, upstream of the initiation codon, and is predicted by multiple computational tools to abolish the canonical 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.4e-05 in 249782 control chromosomes (gnomAD). To our knowledge, no occurrence of c.-17+2T>C in individuals affected with Biotinidase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. While expression of exon 1 is absent in most tissues in the GTEx database, and it is a non-coding exon in the transcript utilized in 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 in a patient affected with partial Biotinidase Deficiency (PMID 29728376) and is cited in 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 (PMID 28649532). 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 (PMID 28649532). A ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics RCV001379913 SCV002811539 likely pathogenic Biotinidase deficiency 2024-04-05 criteria provided, single submitter clinical testing
Baylor Genetics RCV001379913 SCV004211387 uncertain significance Biotinidase deficiency 2025-01-18 criteria provided, single submitter clinical testing This variant, also known as NM_000060.4(BTD):c.44+2T>C, is located at the splicing donor site of exon 1. In the MANE isoform, NM_001370658.1, this variant may impact splicing within the 5' UTR, but the functional consequence is uncertain.
Natera, Inc. RCV001379913 SCV002081542 likely pathogenic Biotinidase deficiency 2017-06-15 no assertion criteria provided clinical testing

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