rs397507173 — BTD

Rare missense variant in the biotinidase enzyme (p.Pro167Ser); a likely pathogenic allele for biotinidase deficiency. Heterozygous carriers have reduced but usually sufficient biotinidase activity; compound heterozygosity with other BTD pathogenic variants can cause partial or profound deficiency requiring lifelong biotin supplementation.

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BTD Pro167Ser — A Rare Pathogenic Allele in the Biotin Recycling Enzyme

Biotin (vitamin B7) is indispensable for four carboxylase enzymes11 carboxylase enzymes
pyruvate carboxylase, propionyl-CoA carboxylase, 3-methylcrotonyl-CoA carboxylase, and acetyl-CoA carboxylase — all require biotin as a covalently attached cofactor to function that power fat synthesis, amino acid metabolism, and gluconeogenesis. Unlike most vitamins, biotin is largely recovered from food proteins rather than absorbed free — the digestive breakdown of biotin-dependent enzymes in the diet releases biocytin22 biocytin
biotin-ε-lysine, the product of proteolytic digestion of holocarboxylases and other biotinylated proteins, which must then be cleaved back to free biotin before the body can reuse it. The enzyme responsible for this cleavage is biotinidase, encoded by the BTD gene on chromosome 3p25.1.

The rs397507173 variant introduces a c.499C>T nucleotide change that substitutes serine for proline at position 167 of the biotinidase protein (p.Pro167Ser). ClinVar records two "Likely pathogenic" submissions for this allele in the context of biotinidase deficiency, with a single "Uncertain significance" submission also on record (VCV003339734; conflicting interpretations status). The variant is absent from more than 250,000 control chromosomes in population databases, consistent with a rare disease allele. It was first documented in patients with biochemically confirmed biotinidase deficiency by Iqbal et al.33 Iqbal et al.
Iqbal F et al. The identification of novel mutations in the biotinidase gene using denaturing high pressure liquid chromatography (dHPLC). Mol Genet Metab, 2010.

The Mechanism

Biotinidase is a member of the nitrilase superfamily. It cleaves the amide bond between biotin and lysine in biocytin, regenerating free biotin for re-attachment to newly synthesized apo-carboxylases. Without functional biotinidase, biocytin accumulates in urine (biotinuria), free biotin concentrations fall, and all four biotin-dependent carboxylases progressively lose activity. The proline at position 167 lies within the enzyme's catalytic domain; replacement with serine is predicted to disrupt local protein folding and reduce or abolish catalytic activity, consistent with ClinVar's pathogenicity assessment and in-silico tools predicting a damaging effect.

Biotinidase deficiency is classified by residual serum enzyme activity: profound deficiency (<10% of mean normal activity) causes severe neurological disease if untreated; partial deficiency (10–30% of mean normal) produces milder or stress-triggered symptoms. Heterozygous carriers typically retain ~50% of normal activity — sufficient for health under ordinary conditions but relevant for compound heterozygosity risk assessment.

The Evidence

The clinical significance of biotinidase deficiency is well established44 well established
Wolf B. Biotinidase Deficiency. GeneReviews, 2000 (updated 2026): untreated profound deficiency causes seizures, hypotonia, developmental delay, optic atrophy, hearing loss, and alopecia, typically presenting in the first weeks to years of life. Biotin supplementation is curative if started before irreversible neurological damage occurs; some deficits (optic atrophy, sensorineural hearing loss) may not fully reverse even with treatment. Partial deficiency can remain asymptomatic for years but cause symptoms under physiological stress — intercurrent illness, pregnancy, or periods of increased biotin turnover.

The rs397507173 Pro167Ser allele itself has been reported in individuals with confirmed biotinidase deficiency, including at least one homozygous case (ClinVar record). Its rarity — absent in 251,442 control chromosomes across gnomAD datasets — and the in-silico evidence of functional disruption support the "likely pathogenic" classification. The conflicting "uncertain significance" submission likely reflects the limited published functional data specific to this single variant, rather than any evidence of benignity.

Newborn screening programs that test biotinidase activity on dried blood spots identify profound deficiency at approximately 1 in 137,000 births and combined (profound + partial) deficiency at 1 in 61,000 births55 1 in 137,000 births and combined (profound + partial) deficiency at 1 in 61,000 births
Wolf B, GeneReviews 2026. BTD is a required target on expanded newborn screening panels in the United States and many European countries precisely because early biotin supplementation is inexpensive, safe, and prevents irreversible harm.

Practical Actions

Heterozygous carriers (CT genotype) have sufficient biotinidase activity for normal health and do not require supplementation. The primary clinical relevance is reproductive: if both parents carry a pathogenic BTD allele, each pregnancy has a 25% probability of inheriting biallelic pathogenic variants and presenting with biotinidase deficiency. Carrier couples should receive genetic counseling before or during pregnancy.

Individuals who carry Pro167Ser in compound heterozygosity with a second pathogenic BTD variant (particularly the common profound-deficiency alleles) should have biotinidase enzyme activity measured to determine their actual activity level and need for supplementation.

For homozygous Pro167Ser (TT) individuals — an exceptionally rare genotype not yet documented in population databases — the expected clinical scenario is profound biotinidase deficiency requiring immediate and lifelong biotin supplementation, as for all confirmed profound cases.

Interactions

The key interactions for BTD pathogenic alleles involve compound heterozygosity: carrying one Pro167Ser allele together with a second BTD pathogenic variant on the other chromosome results in biallelic loss of function, producing partial or profound deficiency depending on the combined residual activity. The most common co-occurring allele in many populations is p.Asp444His (associated with partial deficiency), and the most common severe allele is the c.98_104delinsTCC frameshift. When Pro167Ser is paired with a severe loss-of-function allele, the phenotype is expected to be profound deficiency; paired with the milder p.Asp444His, the combined activity typically falls in the partial deficiency range (approximately 10–25% of normal). Any individual found to carry Pro167Ser should have their partner screened for BTD pathogenic variants before or during pregnancy, and any child of two carriers should receive biotinidase activity testing as part of newborn screening.

Nutrient Interactions

biotin increased_need

Genotype Interpretations

What each possible genotype means for this variant.

CC Non-Carrier Normal

Normal biotinidase function — no BTD Pro167Ser allele

With no copies of the Pro167Ser variant, your BTD gene produces biotinidase with a proline at position 167 — the reference configuration associated with normal catalytic activity. Biotin recycling proceeds without impairment, and standard dietary biotin intake supports normal carboxylase function.

You do not carry a BTD pathogenic allele that could contribute to biotinidase deficiency in your children, unless your partner carries a pathogenic BTD variant (in which case your children could still be carriers of that variant, but not affected by biallelic deficiency from this locus).

TT Homozygous Deficient

Homozygous BTD Pro167Ser — expected profound biotinidase deficiency; immediate evaluation required

Homozygosity for a likely pathogenic BTD allele is expected to produce profound biotinidase deficiency (<10% of mean normal serum biotinidase activity). Without functional biotinidase, biocytin — the product of carboxylase degradation — cannot be cleaved to release free biotin. Free biotin concentrations fall, and all four biotin-dependent carboxylases (pyruvate carboxylase, propionyl-CoA carboxylase, 3-methylcrotonyl-CoA carboxylase, and acetyl-CoA carboxylase) lose their cofactor and become progressively inactive.

Clinically, untreated profound biotinidase deficiency most commonly presents in infancy with seizures, hypotonia, and developmental delay, followed by optic atrophy, sensorineural hearing loss, cutaneous manifestations (seborrheic dermatitis, alopecia), and in severe cases respiratory compromise. Critically, optic atrophy and hearing loss acquired before treatment begins may not fully reverse even with biotin supplementation — early treatment is essential.

Oral free biotin (D-biotin) is the standard treatment. The GeneReviews clinical recommendation for profound deficiency is 5–10 mg/day for infants and children; adult dosing is in the same range. Therapy is lifelong because the genetic inability to recycle biotin does not resolve. With consistent supplementation at an appropriate dose, most metabolic and neurological manifestations resolve or stabilize, and prognosis is good for children treated before irreversible complications.

Note: if you are an adult who has not previously been diagnosed with biotinidase deficiency, this result should be confirmed with serum biotinidase enzyme activity measurement before treatment is initiated, as genotype prediction is not a substitute for biochemical confirmation.

CT Carrier Carrier

Heterozygous carrier of BTD Pro167Ser — reduced enzyme activity, typically asymptomatic

Biotinidase deficiency is an autosomal recessive condition: two pathogenic BTD alleles are required to cause disease. With one functional allele and one Pro167Ser allele, your biotinidase activity is expected to fall in the intermediate range — roughly half of normal. This is sufficient to recycle free biotin for all four carboxylase enzymes under typical dietary and metabolic conditions.

The clinically significant scenario for carriers is compound heterozygosity: if your other BTD allele is also pathogenic (a second mutation not detected at this position), the combined residual activity could fall into the partial or profound deficiency range. If your partner also carries a pathogenic BTD variant, each pregnancy has a 25% chance of producing a child with biallelic BTD pathogenic variants and biotinidase deficiency.

Neonatal biotinidase activity testing (included in expanded newborn screening panels in many countries) would identify any affected child before symptoms appear. Early biotin supplementation is curative when started promptly.