# NM_000108.5(DLD):c.1187_1188del (p.His396fs)

https://sugi.bio/variant/dld-p-his396fs

## Summary

**DLD p.His396fs (c.1187_1188del)** is classified **Likely pathogenic** in DLD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-01). No gnomAD frequency available for this variant; Associated with pyruvate dehydrogenase E3 deficiency.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2535602632 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the DLD gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to pyruvate dehydrogenase E3 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) | Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Worldwide) |
| Diagnostic panels | DLD is a diagnostic-grade gene on 12 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/0003263/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DLD](https://sugi.bio/atlas/gene/DLD/) |
| Protein change (HGVS p.) | p.His396fs |
| Coding change (HGVS c.) | c.1187_1188del |
| MANE Select transcript | [NM_000108](https://www.ncbi.nlm.nih.gov/nuccore/NM_000108) |
| dbSNP | [rs2535602632](https://www.ncbi.nlm.nih.gov/snp/rs2535602632/) |
| Variant type | Microsatellite |
| Location | chr7:107917407-107917408 (GRCh38) |
| ClinVar | [VCV1726989](https://www.ncbi.nlm.nih.gov/clinvar/variation/1726989/) |

**All HGVS expressions:** `NC_000007.13:g.107557852AC[3]`, `NC_000007.14:g.107917407AC[3]`, `NG_008045.1:g.31267AC[3]`, `NM_000108.5:c.1187_1188del`, `NM_001289750.1:c.890_891del`, `NM_001289751.1:c.1118_1119del`, `NM_001289752.1:c.1043_1044del`

## 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 6.219, GERP 2.07, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.727, pLI 0.00025663. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 11 of 14**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite 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}

**DLD** population constraint: LOEUF 0.727, pLI 0.00025663, missense-Z 1.5317. *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** — Definitive (AR)
- **pyruvate dehydrogenase E3 deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **396** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 93.69, 92% of residues very-high.

**17 experimental structure(s)** (PDB): [1ZMC](https://www.rcsb.org/structure/1ZMC), [1ZMD](https://www.rcsb.org/structure/1ZMD), [1ZY8](https://www.rcsb.org/structure/1ZY8), [2F5Z](https://www.rcsb.org/structure/2F5Z), [3RNM](https://www.rcsb.org/structure/3RNM), [5J5Z](https://www.rcsb.org/structure/5J5Z) — incl. mutant structure 5J5Z.

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

*Describes the biological roles of DLD (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:** DLD's established molecular role includes dihydrolipoyl dehydrogenase (NADH) activity. In Reactome, DLD is annotated in disease pathway(s) including **Branched-chain ketoacid dehydrogenase kinase deficiency**, **H139Hfs13* PPM1K causes a mild variant of  MSUD**.

**Disease mechanism (Reactome):** DLD 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 DBT cause MSUD2](https://reactome.org/content/detail/R-HSA-9865113).

### Pathways affected {#pathways}

DLD participates in **13 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 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 |
| [Glycine degradation](https://reactome.org/content/detail/R-HSA-6783984) | curated |
| [Mitochondrial protein degradation](https://reactome.org/content/detail/R-HSA-9837999) | curated |
| [OADH complex synthesizes glutaryl-CoA from 2-OA](https://reactome.org/content/detail/R-HSA-9858328) | curated |
| [OGDH complex synthesizes succinyl-CoA from 2-OG](https://reactome.org/content/detail/R-HSA-9853506) | curated |
| [PDH complex synthesizes acetyl-CoA from PYR](https://reactome.org/content/detail/R-HSA-9861559) | curated |
| [Regulation of pyruvate dehydrogenase (PDH) complex](https://reactome.org/content/detail/R-HSA-204174) | curated |
| [Signaling by Retinoic Acid](https://reactome.org/content/detail/R-HSA-5362517) | curated |

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

**Molecular function:** dihydrolipoyl dehydrogenase (NADH) activity.

**Biological process:** pyruvate decarboxylation to acetyl-CoA, branched-chain amino acid catabolic process, obsolete L-lysine catabolic process to acetyl-CoA, 2-oxoglutarate decarboxylation to succinyl-CoA, 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 2022-04-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Myriad Genetics, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-04-01 |

## Associated conditions {#conditions}

[pyruvate dehydrogenase E3 deficiency](https://sugi.bio/atlas/disease/pyruvate-dehydrogenase-e3-deficiency/).

**Reported phenotype names (ClinVar):** Pyruvate dehydrogenase E3 deficiency, Dihydrolipoamide Dehydrogenase (E3) Deficiency, Lipoamide dehydrogenase deficiency, lactic acidosis due to, Lipoamide dehydrogenase deficiency, DLD DEFICIENCY, E3 DEFICIENCY, Dihydrolipoamide Dehydrogenase Deficiency, Dihydrolipoamide Dehydrogenase E3 Deficiency, MAPLE SYRUP URINE DISEASE, TYPE III.

## Similar variants {#similar}

Related DLD variant pages (same residue, condition, or type): [DLD p.Asp448fs](/variant/dld-p-asp448fs), [DLD p.His96fs](/variant/dld-p-his96fs), [DLD c.337+4_337+7del](/variant/dld-c-337-plus-4-337-plus-7del), [DLD p.Arg482fs](/variant/dld-p-arg482fs), [DLD p.Leu76fs](/variant/dld-p-leu76fs), [DLD p.Tyr8fs](/variant/dld-p-tyr8fs), [DLD c.685-8_685-5del](/variant/dld-c-685-minus-8-685-minus-5del), [DLD p.Ile507fs](/variant/dld-p-ile507fs).

### 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 1726989). 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.*