# NM_001918.5(DBT):c.206T>C (p.Leu69Pro)

https://sugi.bio/variant/dbt-p-leu69pro

## Summary

**DBT p.Leu69Pro (c.206T>C)** is classified **Conflicting classifications of pathogenicity** in DBT (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-14). AlphaMissense: likely pathogenic (0.9985); Very rare (popmax 0.000171%, nfe); Associated with maple syrup urine disease.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1663813561 · 4 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.000171%, nfe)

## For patients & families {#patients}

This is a change in the DBT gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, and is linked to maple syrup urine disease.

*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) | Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Worldwide) |
| Clinical trials | 11 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | DBT is a diagnostic-grade gene on 10 Genomics England panels |

**Commonly reported features of Maple syrup urine disease** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of the pharynx — Very frequent (99-80%)
- Intellectual disability — Very frequent (99-80%)
- Seizure — Very frequent (99-80%)
- Hypotonia — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- Reduced tendon reflexes — Very frequent (99-80%)
- Abnormality of the voice — Very frequent (99-80%)
- Respiratory insufficiency — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003228/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DBT](https://sugi.bio/atlas/gene/DBT/) |
| Protein change (HGVS p.) | p.Leu69Pro |
| Coding change (HGVS c.) | c.206T>C |
| MANE Select transcript | [NM_001918](https://www.ncbi.nlm.nih.gov/nuccore/NM_001918) |
| dbSNP | [rs1663813561](https://www.ncbi.nlm.nih.gov/snp/rs1663813561/) |
| Variant type | single nucleotide variant |
| Location | chr1:100235481-100235481 (GRCh38) |
| ClinVar | [VCV1502605](https://www.ncbi.nlm.nih.gov/clinvar/variation/1502605/) |

**All HGVS expressions:** `NC_000001.10:g.100701037A>G`, `NC_000001.11:g.100235481A>G`, `NG_011852.2:g.19373T>C`, `NM_001918.5:c.206T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9985)
- REVEL 0.748 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.623 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.047, GERP 2.57, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in DBT (of 2,832 modeled).
- CADD: **PHRED 29.1**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.88** across the covering region of the MANE Select transcript (100,196,258–100,249,820), spanning 53,562 bp. Chi-square p 0.0036. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000171%** (nfe) · FAF95 2.9e-05% · FAF99 1.1e-05% · 2/1,166,460 in the highest group · 2/1,597,738 alleles overall — very rare (popmax 0.000171%, nfe).

*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}

**DBT** population constraint: LOEUF 1.255, pLI 3.6458e-09, missense-Z 1.3238; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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):

- **maple syrup urine disease** — Definitive (AR)

## Protein context {#protein}

Residue **69** lies in the lipoyl-binding domain.

AlphaFold model confidence (whole protein): pLDDT 78.71, 55% of residues very-high.

**5 experimental structure(s)** (PDB): [1K8M](https://www.rcsb.org/structure/1K8M), [1K8O](https://www.rcsb.org/structure/1K8O), [1ZWV](https://www.rcsb.org/structure/1ZWV), [2COO](https://www.rcsb.org/structure/2COO), [3RNM](https://www.rcsb.org/structure/3RNM).

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

*Describes the biological roles of DBT (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:** DBT's established molecular role includes ubiquitin protein ligase binding. p.Leu69Pro falls in the lipoyl-binding domain. In Reactome, DBT is annotated in disease pathway(s) including **Branched-chain ketoacid dehydrogenase kinase deficiency**, **H139Hfs13* PPM1K causes a mild variant of  MSUD**.

**Disease mechanism (Reactome):** DBT loss or alteration is curated in [Branched-chain ketoacid dehydrogenase kinase deficiency](https://reactome.org/content/detail/R-HSA-9912481), [H139Hfs13* PPM1K causes a mild variant of  MSUD](https://reactome.org/content/detail/R-HSA-9912529), [Loss-of-function mutations in BCKDHA or BCKDHB cause MSUD](https://reactome.org/content/detail/R-HSA-9865125).

### Pathways affected {#pathways}

DBT participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Branched-chain ketoacid dehydrogenase kinase deficiency](https://reactome.org/content/detail/R-HSA-9912481) | curated |
| ⚕ [H139Hfs13* PPM1K causes a mild variant of  MSUD](https://reactome.org/content/detail/R-HSA-9912529) | curated |
| ⚕ [Loss-of-function mutations in BCKDHA or BCKDHB cause MSUD](https://reactome.org/content/detail/R-HSA-9865125) | curated |
| ⚕ [Loss-of-function mutations in DBT cause MSUD2](https://reactome.org/content/detail/R-HSA-9865113) | curated |
| ⚕ [Loss-of-function mutations in DLD cause MSUD3/DLDD](https://reactome.org/content/detail/R-HSA-9907570) | curated |
| [BCKDH synthesizes BCAA-CoA from KIC, KMVA, KIV](https://reactome.org/content/detail/R-HSA-9859138) | curated |
| [Branched-chain amino acid catabolism](https://reactome.org/content/detail/R-HSA-70895) | curated |
| [Mitochondrial protein degradation](https://reactome.org/content/detail/R-HSA-9837999) | curated |
| [Protein lipoylation](https://reactome.org/content/detail/R-HSA-9857492) | curated |
| [RHOH GTPase cycle](https://reactome.org/content/detail/R-HSA-9013407) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** ubiquitin protein ligase binding.

**Biological process:** branched-chain amino acid catabolic process, branched-chain alpha-keto acid decarboxylation to branched-chain acyl-CoA.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-11-14.

**Submitter consensus:** conflicting (2 Likely pathogenic, 1 Pathogenic, 1 Uncertain significance).

**Submission history:** 4 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-12-26 |
| Mendelics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-04 |
| Genome-Nilou Lab | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-04-11 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-14 |

## Associated conditions {#conditions}

[maple syrup urine disease](https://sugi.bio/atlas/disease/maple-syrup-urine-disease/).

**Reported phenotype names (ClinVar):** Maple syrup urine disease, not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related DBT variant pages (same residue, condition, or type): [DBT p.Leu69=](/variant/dbt-p-leu69), [DBT p.Leu69Arg](/variant/dbt-p-leu69arg), [DBT c.1018-550A>G](/variant/dbt-c-1018-minus-550a-g), [DBT c.1281+1G>A](/variant/dbt-c-1281-plus-1g-a), [DBT c.1281+1G>T](/variant/dbt-c-1281-plus-1g-t), [DBT c.51+1G>T](/variant/dbt-c-51-plus-1g-t), [DBT c.52-1G>A](/variant/dbt-c-52-minus-1g-a), [DBT p.Arg291Ter](/variant/dbt-p-arg291ter).

### 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 1502605). 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.*