# NM_001370658.1(BTD):c.91_92del (p.Asp31fs)

https://sugi.bio/variant/btd-p-asp31fs

## Summary

**BTD p.Asp31fs (c.91_92del)** is classified **Likely pathogenic** in BTD (ClinVar, Single submitter, 1 submitter). No gnomAD frequency available for this variant; Associated with biotinidase deficiency.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2471440173 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the BTD gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to biotinidase deficiency.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Worldwide) |
| Clinical trials | 7 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | BTD is a diagnostic-grade gene on 14 Genomics England panels |

**Commonly reported features of Biotinidase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Organic aciduria — Very frequent (99-80%)
- Metabolic ketoacidosis — Very frequent (99-80%)
- Decreased biotinidase activity — Very frequent (99-80%)
- Sensorineural hearing impairment — Frequent (79-30%)
- Abnormality of the nervous system — Frequent (79-30%)
- Skin rash — Frequent (79-30%)
- Seizure — Frequent (79-30%)
- Hypotonia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000894/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BTD](https://sugi.bio/atlas/gene/BTD/) |
| Protein change (HGVS p.) | p.Asp31fs |
| Coding change (HGVS c.) | c.91_92del |
| MANE Select transcript | [NM_001370658](https://www.ncbi.nlm.nih.gov/nuccore/NM_001370658) |
| dbSNP | [rs2471440173](https://www.ncbi.nlm.nih.gov/snp/rs2471440173/) |
| Variant type | Deletion |
| Location | chr3:15635530-15635531 (GRCh38) |
| ClinVar | [VCV3234871](https://www.ncbi.nlm.nih.gov/clinvar/variation/3234871/) |

**All HGVS expressions:** `NC_000003.11:g.15677037_15677038del`, `NC_000003.12:g.15635530_15635531del`, `NG_008019.2:g.39179_39180del`, `NG_008019.3:g.39180_39181del`, `NM_000060.4:c.151_152delGA`, `NM_001281723.4:c.91_92del`, `NM_001281724.3:c.91_92del`, `NM_001281725.3:c.91_92del`, `NM_001281726.3:c.91_92del`, `NM_001323582.2:c.91_92del`, `NM_001370658.1:c.91_92del`, `NM_001370752.1:c.91_92del`, `NM_001370753.1:c.91_92del`, `NM_001407364.1:c.91_92del`, `NM_001407365.1:c.91_92del`, `NM_001407366.1:c.91_92del`, `NM_001407367.1:c.91_92del`, `NM_001407368.1:c.91_92del`, `NM_001407369.1:c.91_92del`, `NM_001407370.1:c.91_92del`, `NM_001407371.1:c.91_92del`, `NM_001407372.1:c.91_92del`, `NM_001407373.1:c.91_92del`, `NM_001407374.1:c.91_92del`, `NM_001407375.1:c.91_92del`, `NM_001407376.1:c.91_92del`, `NM_001407377.1:c.91_92del`, `NM_001407378.1:c.91_92del`, `NM_001407379.1:c.91_92del`, `NM_001407380.1:c.91_92del`, `NM_001407381.1:c.91_92del`, `NM_001407382.1:c.91_92del`, `NM_001407383.1:c.91_92del`, `NM_001407384.1:c.91_92del`, `NM_001407386.1:c.91_92del`, `NM_001407388.1:c.91_92del`, `NM_001407390.1:c.91_92del`, `NM_001407392.1:c.91_92del`, `NM_001407394.1:c.91_92del`, `NM_001407395.1:c.91_92del`, `NM_001407396.1:c.91_92del`, `NM_001407397.1:c.91_92del`, `NM_001407398.1:c.91_92del`, `NM_001407399.1:c.91_92del`, `NM_001407400.1:c.91_92del`, `NM_001407401.1:c.91_92del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -9.562, GERP -1.81 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.22, pLI 5.4385e-05. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 4**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**BTD** population constraint: LOEUF 1.22, pLI 5.4385e-05, missense-Z 0.16275. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Leigh syndrome** — Moderate (AR)
- **biotinidase deficiency** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 86.77, 79% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of BTD (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** BTD participates in disease-associated pathways. In Reactome, BTD is annotated in disease pathway(s) including **Defective BTD causes biotidinase deficiency**.

**Disease mechanism (Reactome):** BTD loss or alteration is curated in [Defective BTD causes biotidinase deficiency](https://reactome.org/content/detail/R-HSA-3371598).

### Pathways affected {#pathways}

BTD participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective BTD causes biotidinase deficiency](https://reactome.org/content/detail/R-HSA-3371598) | curated |
| [Biotin transport and metabolism](https://reactome.org/content/detail/R-HSA-196780) | curated |

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Neuberg Centre For Genomic Medicine, NCGM | Likely pathogenic | criteria provided, single submitter | clinical testing |  |

## Associated conditions {#conditions}

[biotinidase deficiency](https://sugi.bio/atlas/disease/biotinidase-deficiency/).

**Reported phenotype names (ClinVar):** Biotinidase deficiency, Biotin deficiency, BTD deficiency, Late-onset biotin-responsive multiple carboxylase deficiency.

## Similar variants {#similar}

Related BTD variant pages (same residue, condition, or type): [BTD c.250-15del](/variant/btd-c-250-minus-15del), [BTD p.Arg144fs](/variant/btd-p-arg144fs), [BTD p.Arg442fs](/variant/btd-p-arg442fs), [BTD p.Arg502fs](/variant/btd-p-arg502fs), [BTD p.Cys15fs](/variant/btd-p-cys15fs), [BTD p.Gln116fs](/variant/btd-p-gln116fs), [BTD p.Gly14fs](/variant/btd-p-gly14fs), [BTD p.Gly431fs](/variant/btd-p-gly431fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 3234871). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*