Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PM2PM5PP2PP5_Very_Strong
The NM_001370658.1(BTD):c.704T>C(p.Ile235Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I235M) has been classified as Likely pathogenic.
BTD (HGNC:1122): (biotinidase) The protein encoded by this gene functions to recycle protein-bound biotin by cleaving biocytin (biotin-epsilon-lysine), a normal product of carboxylase degradation, resulting in regeneration of free biotin. The encoded protein has also been shown to have biotinyl transferase activity. Mutations in this gene are associated with biotinidase deficiency. Multiple transcript variants encoding different isoforms have been described. [provided by RefSeq, Aug 2013]
Our verdict: Pathogenic. The variant received 15 ACMG points.
PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001370658.1
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-15644621-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 801946.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 88 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: -0.52516 (below the threshold of 3.09). Trascript score misZ: 0.15371 (below the threshold of 3.09). GenCC associations: The gene is linked to Leigh syndrome, biotinidase deficiency.
PP5
Variant 3-15644620-T-C is Pathogenic according to our data. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644620-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 25040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Variant summary: BTD c.704T>C (p.Ile235Thr) results in a non-conservative amino acid change located in the Carbon-nitrogen hydrolase domain (IPR003010) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251440 control chromosomes (gnomAD). c.704T>C has been reported in the literature in at least three compound heterozygous individuals affected with Biotinidase Deficiency (Ohlsson_2010, Jay_2015), who carried a pathogenic variant in trans. In one of the reported patients the biotinidase activity in plasma was immeasurable, suggesting this variant results in profound Biotinidase deficiency (Ohlsson_2010). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as likely pathogenic, or as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Aug 21, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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. 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. ClinVar contains an entry for this variant (Variation ID: 25040). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 20224900, 25144890; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs397514384, gnomAD 0.002%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 255 of the BTD protein (p.Ile255Thr). -
Mar 28, 2018
Counsyl
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method: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. -