Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003230341 | SCV003929213 | uncertain significance | not specified | 2023-04-28 | criteria provided, single submitter | clinical testing | Variant summary: BTD c.1406A>C (p.Asn469Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three 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 251444 control chromosomes. c.1406A>C has been reported in the literature as a homozygous genotype in at-least one individual affected with Biotinidase Deficiency (example, Pomponio_1998). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28498829, 20556795, 9705240). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=3; LP, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Gene |
RCV002272006 | SCV002558646 | uncertain significance | not provided | 2022-01-26 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9705240, 20556795) |
| Labcorp Genetics |
RCV000001980 | SCV002288117 | likely pathogenic | Biotinidase deficiency | 2024-03-13 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 489 of the BTD protein (p.Asn489Thr). This variant is present in population databases (rs104893692, gnomAD 0.02%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 9705240; Invitae). 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: 1903). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BTD protein function with a positive predictive value of 80%. This variant disrupts the p.Asn489 amino acid residue in BTD. Other variant(s) that disrupt this residue have been observed in individuals with BTD-related conditions (PMID: 28498829), which suggests that this may be a clinically significant amino acid residue. 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. |
| Counsyl | RCV000001980 | SCV000800649 | uncertain significance | Biotinidase deficiency | 2018-01-05 | no assertion criteria provided | clinical testing | This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. |
| OMIM | RCV000001980 | SCV000022138 | pathogenic | Biotinidase deficiency | 1998-06-01 | no assertion criteria provided | literature only |