rs397514384
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP5
The NM_001370658.1(BTD):āc.704T>Cā(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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I235M) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001370658.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BTD | NM_001370658.1 | c.704T>C | p.Ile235Thr | missense_variant | 4/4 | ENST00000643237.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BTD | ENST00000643237.3 | c.704T>C | p.Ile235Thr | missense_variant | 4/4 | NM_001370658.1 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251440Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135896
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461894Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727248
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74346
ClinVar
Submissions by phenotype
Biotinidase deficiency Pathogenic:3Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 11, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 17, 2023 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 21, 2023 | 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. 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). This variant is present in population databases (rs397514384, gnomAD 0.002%). 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. ClinVar contains an entry for this variant (Variation ID: 25040). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 28, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at