rs397507172 — BTD

BTD Val89Gly — A Rare Variant Near the Biotinidase Catalytic Site

Every time your body breaks down a protein that used biotin as a cofactor, it produces biocytin — a biotin molecule still attached to a lysine residue. Recovering that biotin for reuse is the job of biotinidase¹¹ biotinidase
the enzyme encoded by the BTD gene on chromosome 3p25.1; it cleaves the amide bond between biotin and lysine in biocytin, releasing free biotin for re-loading onto the next carboxylase enzyme. When biotinidase activity falls too low, biotin cannot be recycled, and the four biotin-dependent carboxylases — pyruvate carboxylase, propionyl-CoA carboxylase, 3-methylcrotonyl-CoA carboxylase, and acetyl-CoA carboxylase — begin to fail, disrupting fatty acid synthesis, gluconeogenesis, and amino acid catabolism simultaneously.

The rs397507172 variant substitutes glycine for valine at position 89 of the biotinidase protein (p.Val89Gly, c.266T>G). It is extremely rare — essentially absent in population databases — and was observed in a newborn screening cohort²² newborn screening cohort
Mühl A et al. Molecular characterisation of 34 patients with biotinidase deficiency ascertained by newborn screening and family investigation. Eur J Hum Genet, 2001 investigating the spectrum of BTD mutations in Austria.

The Mechanism

The BTD protein is a 523-amino-acid serine hydrolase containing three catalytic residues: His92 (proton acceptor), Asp192 (proton donor), and Ser225 (nucleophile). Val89 sits only three positions upstream of the catalytic His92. The substitution of a bulky, hydrophobic valine with the tiny, conformationally flexible glycine at position 89 is expected to destabilize the local α-helix and alter the positioning of the active-site histidine.

In vitro activity studies³³ In vitro activity studies
Borsatto T et al. Effect of BTD gene variants on in vitro biotinidase activity. Mol Genet Metab, 2019 across a range of BTD missense variants demonstrated that mutations close to the catalytic triad consistently produce severe reductions in enzyme activity — the p.Leu40Pro variant (also near the N-terminal region) showed 33% intracellular and only 7% extracellular activity, while p.Cys160Tyr produced 14% and 0.3%, respectively. No direct in vitro measurement is available for Val89Gly, but its proximity to His92 makes functional disruption biologically plausible. This variant has not been entered into ClinVar as of April 2026; it is formally classified as a variant of uncertain significance pending enzyme activity confirmation.

The Evidence

Biotinidase deficiency follows autosomal recessive inheritance. The clinical framework rests on enzyme activity thresholds established by Wolf and colleagues⁴⁴ Wolf and colleagues
Wolf B. Biotinidase Deficiency. GeneReviews, 2026. Updated February 19, 2026: profound deficiency is defined as <10% of mean normal serum biotinidase activity, partial deficiency as 10–30%. Heterozygous carriers (one functional allele, one variant allele) typically show ~50% of normal activity and are asymptomatic; they do not require biotin therapy and are not at risk for the disorder.

The clinical significance of rs397507172 for heterozygous carriers is therefore limited to reproductive counseling: if both partners carry a pathogenic BTD allele, each pregnancy faces a 25% chance of biallelic inheritance and clinical deficiency. A large reproductive carrier screening study⁵⁵ reproductive carrier screening study
Benn P et al. Evaluating reproductive carrier screening using biotinidase deficiency as a model. Genet Med, 2025 of 91,637 women found 6.1% carry at least one P/LP BTD variant, underscoring the importance of partner testing when a BTD variant is identified.

Practical Actions

For heterozygous carriers, the primary action is genetic counseling and partner testing. No biotin supplementation is required under normal conditions. If a partner is also found to carry a pathogenic BTD variant, preconception or prenatal testing options should be discussed.

For the extremely rare case of homozygous or compound heterozygous inheritance, the treatment is pharmacological biotin supplementation: 5–10 mg/day oral free biotin for profound deficiency, 2.5–10 mg/day for partial deficiency. Because neonatal biotin stores are depleted within the first few weeks of life without recycling, enzyme activity testing and treatment should begin in the newborn period. All children born in countries with universal newborn screening will be identified if they have significant biotinidase deficiency; genetic testing of parents and siblings after a proband is found adds important reproductive risk information.

Interactions

BTD is an autosomal recessive gene, so compound heterozygosity matters: a carrier of rs397507172 (one G allele) who also carries a second pathogenic BTD variant on the other chromosome — particularly a severe allele causing profound deficiency — could produce offspring with partial or profound biotinidase deficiency. The D444H allele (rs13078881, the most common partial-deficiency allele at ~3.9% population frequency per Swango et al.⁶⁶ Swango et al.) is the most likely partner allele in compound heterozygous scenarios.