Description
Variant summary: BTD c.1147T>G (p.Phe383Val), also known as c.1207T>G (p.Phe403Val), results in a non-conservative amino acid change located in the vanin, C-terminal domain (IPR043957) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251384 control chromosomes (gnomAD). c.1147T>G has been reported in the literature, frequently observed in cis with c.1270G>C (p.Asp424His, also known as p.Asp444His), in multiple individuals affected with Biotinidase Deficiency, including several cases where the variant was observed in the homozygous state in cis with p.Asp424His in patients with profound Biotinidase Deficiency (e.g. Norrgard_1999, Hesermann_2012, Al Hosani_2014, Haines_2014, Jay_2015, Al-Jasmi_2016, Khan_2021, Saleh_2021). p.Asp424His is known to be associated with partial Biotinidase deficiency when in compound heterozygosity with other BTD variants associated with a mild or a severe phenotype, while homozygous individuals are expected to be unaffected (as described in ClinVar submission by our laboratory, SCV001363363.2). Given p.Asp424His is linked to partial Biotinidase deficiency, and provided that homozygous patients with [F383V;D424H] showed profound biotinidase deficiency, the variant of interest is implied to have an adverse effect on enzyme function. These data indicate that the variant is likely to be associated with disease. Of interest is a recent report by Hou et al (2020), describing the variant in a compound heterozygosity with p.Asp424His in an individual with no associated disease phenotype. The following publications have been ascertained in the context of this evaluation (PMID: 26589311, 24516753, 24932929, 22698809, 24525934, 31980526, 25144890, 34166817, 10400129, 34374989). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Two classified the variant as pathogenic/likely pathogenic, and one classified it as uncertain significance. 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 |
