Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV005139558 | SCV005768525 | pathogenic | Biotinidase deficiency | 2025-01-26 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 311 of the BTD protein (p.Ser311Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 10400129; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt BTD protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. |
| ARUP Laboratories, |
RCV005139558 | SCV005877362 | likely pathogenic | Biotinidase deficiency | 2024-10-14 | criteria provided, single submitter | clinical testing | The BTD c.872G>A; p.Ser291Asn variant (rs397514394), also known as c.932G>A; p.Ser311Asn for NM_000060.2, is reported in the literature in several individuals affected with biotinidase deficiency (Kannan 2022, Norrgard 1999). At least one patient carried a second pathogenic allele and exhibited substantially reduced serum biotinidase activity (Norrgard 1999). The p.Ser291Asn variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.827). Additionally, other variants at this codon (c.873T:G, p.Ser291Arg; c.872G>C, p.Ser291Thr) have been reported in individuals with biotinidase deficiency and are considered disease-causing (Carvalho 2019, Iqbal 2010, Kannan 2022). Based on available information, the p.Ser291Asn variant is considered to be likely pathogenic. References: Carvalho NO et al. Novel mutations causing biotinidase deficiency in individuals identified by the newborn screening program in Minas Gerais, Brazil. Am J Med Genet A. 2019 Jun;179(6):978-982. PMID: 30912303. Iqbal F et al. The identification of novel mutations in the biotinidase gene using denaturing high pressure liquid chromatography (dHPLC). Mol Genet Metab. 2010 May;100(1):42-5. PMID: 20083419. Kannan B et al. A Rare Biotinidase Deficiency in the Pediatrics Population: Genotype-Phenotype Analysis. J Pediatr Genet. 2022 Nov 1;12(1):1-15. PMID: 36684547. Norrgard KJ et al. Mutations causing profound biotinidase deficiency in children ascertained by newborn screening in the United States occur at different frequencies than in symptomatic children. Pediatr Res. 1999 Jul;46(1):20-7. PMID: 10400129. |