Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000414058 | SCV000492140 | likely pathogenic | not provided | 2016-11-21 | criteria provided, single submitter | clinical testing | The R148C missense variant in the BTD gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R148C variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R148C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved; however, a missense variant at the same position (R148H) has been reported in association with biotinidase deficiency in the Human Gene Mutation Database and the ARUP mutation database (http://www.arup.utah.edu/database/BTD/BTD_welcome.php), and missense variants in nearby residues (C143F, F149L, T152P, T152R) have also been reported in the two databases in association with biotinidase deficiency, supporting the functional importance of this region of the protein. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function; although, the majority of models predict R148C to be damaging. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. |
| Labcorp Genetics |
RCV000675064 | SCV003516494 | uncertain significance | Biotinidase deficiency | 2022-10-13 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 148 of the BTD protein (p.Arg148Cys). This variant is present in population databases (rs137877018, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with BTD-related conditions. ClinVar contains an entry for this variant (Variation ID: 373539). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Counsyl | RCV000675064 | SCV000800535 | uncertain significance | Biotinidase deficiency | 2017-05-12 | no assertion criteria provided | clinical testing |