# NM_001918.5(DBT):c.1346C>G (p.Ser449Ter)

https://sugi.bio/variant/dbt-p-ser449ter

## Summary

**DBT p.Ser449Ter (c.1346C>G)** is classified **Likely pathogenic** in DBT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-29). Absent from gnomAD v4.1; Associated with maple syrup urine disease type 2.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2524063471 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DBT gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to maple syrup urine disease type 2.

*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) |
| 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/0008596/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.Ser449Ter |
| Coding change (HGVS c.) | c.1346C>G |
| MANE Select transcript | [NM_001918](https://www.ncbi.nlm.nih.gov/nuccore/NM_001918) |
| dbSNP | [rs2524063471](https://www.ncbi.nlm.nih.gov/snp/rs2524063471/) |
| Variant type | single nucleotide variant |
| Location | chr1:100196358-100196358 (GRCh38) |
| ClinVar | [VCV3065883](https://www.ncbi.nlm.nih.gov/clinvar/variation/3065883/) |

**All HGVS expressions:** `NC_000001.10:g.100661914G>C`, `NC_000001.11:g.100196358G>C`, `NG_011852.2:g.58496C>G`, `NG_011852.3:g.58476C>G`, `NM_001399969.1:c.803C>G`, `NM_001399972.1:c.803C>G`, `NM_001918.5:c.1346C>G`, `NR_174363.1:n.1178C>G`, `NR_174364.1:n.1519C>G`, `NR_174365.1:n.1143C>G`, `NR_174366.1:n.1445C>G`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 11.772, GERP 2.1, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.255, pLI 3.6458e-09. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (11 of 11)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- CADD: **PHRED 39.0**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.31 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}


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. 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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-29.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-03-29 |

## Associated conditions {#conditions}

[maple syrup urine disease type 2](https://sugi.bio/atlas/disease/maple-syrup-urine-disease-type-2/).

**Reported phenotype names (ClinVar):** Maple syrup urine disease type 2, Maple syrup urine disease, type II.

## Similar variants {#similar}

Related DBT variant pages (same residue, condition, or type): [DBT p.Ser449=](/variant/dbt-p-ser449), [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.51+1G>T](/variant/dbt-c-51-plus-1g-t), [DBT c.773-2A>G](/variant/dbt-c-773-minus-2a-g), [DBT p.Arg169Ter](/variant/dbt-p-arg169ter), [DBT p.Arg301Cys](/variant/dbt-p-arg301cys), [DBT p.Arg376Cys](/variant/dbt-p-arg376cys).

### 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 3065883). 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.*