# NM_004006.3(DMD):c.10033_10034insTT (p.Arg3345fs)

https://sugi.bio/variant/dmd-p-arg3345fs

## Summary

**DMD p.Arg3345fs (c.10033_10034insTT)** is classified **Likely pathogenic** in DMD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-04). Associated with Duchenne muscular dystrophy.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the DMD gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to Duchenne muscular dystrophy.

*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) | X-linked recessive |
| Age of onset (of this condition) | Childhood |
| Prevalence | 1-9 / 100 000 (Worldwide) |
| Clinical trials | 373 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | DMD is a diagnostic-grade gene on 17 Genomics England panels |

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

- Delayed speech and language development — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- Motor delay — Very frequent (99-80%)
- Specific learning disability — Very frequent (99-80%)
- Flexion contracture — Very frequent (99-80%)
- Cardiomyopathy — Very frequent (99-80%)
- Respiratory insufficiency — Very frequent (99-80%)
- Waddling gait — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006291/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DMD](https://sugi.bio/atlas/gene/DMD/) |
| Protein change (HGVS p.) | p.Arg3345fs |
| Coding change (HGVS c.) | c.10033_10034insTT |
| MANE Select transcript | [NM_004006](https://www.ncbi.nlm.nih.gov/nuccore/NM_004006) |
| Variant type | Insertion |
| Location | chrX:31180422-31180423 (GRCh38) |
| ClinVar | [VCV3896838](https://www.ncbi.nlm.nih.gov/clinvar/variation/3896838/) |

**All HGVS expressions:** `LRG_199:g.2164187_2164188insTT`, `LRG_199t1:c.10033_10034insTT`, `NC_000023.10:g.31198539_31198540insAA`, `NC_000023.11:g.31180422_31180423insAA`, `NG_012232.1:g.2164187_2164188insTT`, `NM_000109.4:c.10009_10010insTT`, `NM_004006.3:c.10033_10034insTT`, `NM_004009.3:c.10021_10022insTT`, `NM_004010.3:c.9664_9665insTT`, `NM_004011.4:c.6010_6011insTT`, `NM_004012.4:c.6001_6002insTT`, `NM_004013.3:c.2653_2654insTT`, `NM_004014.3:c.1846_1847insTT`, `NM_004015.3:c.829_830insTT`, `NM_004016.3:c.829_830insTT`, `NM_004017.3:c.829_830insTT`, `NM_004018.3:c.829_830insTT`, `NM_004019.3:c.829_830insTT`, `NM_004020.4:c.2653_2654insTT`, `NM_004021.3:c.2653_2654insTT`, `NM_004022.3:c.2653_2654insTT`, `NM_004023.3:c.2653_2654insTT`

## 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 7.697, GERP 3.36, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 69 of 79**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no insertion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**DMD** population constraint: ClinGen dosage — haploinsufficiency 3, 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):

- **progressive muscular dystrophy** — Definitive (XL)

## Protein context {#protein}

Residue **3345** lies in the 'interaction with synm' region.

**6 experimental structure(s)** (PDB): [1DXX](https://www.rcsb.org/structure/1DXX), [1EG3](https://www.rcsb.org/structure/1EG3), [1EG4](https://www.rcsb.org/structure/1EG4), [3UUN](https://www.rcsb.org/structure/3UUN), [9D58](https://www.rcsb.org/structure/9D58), [9EC1](https://www.rcsb.org/structure/9EC1).

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

*Describes the biological roles of DMD (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:** DMD's established molecular role includes dystroglycan binding. p.Arg3345fs falls in the interaction with synm region.


### Pathways affected {#pathways}

DMD participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Striated Muscle Contraction](https://reactome.org/content/detail/R-HSA-390522) | curated |
| [Formation of the dystrophin-glycoprotein complex (DGC)](https://reactome.org/content/detail/R-HSA-9913351) | electronic |
| [Non-integrin membrane-ECM interactions](https://reactome.org/content/detail/R-HSA-3000171) | electronic |

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

**Molecular function:** dystroglycan binding, actin binding, structural constituent of muscle, myosin binding, vinculin binding.

**Biological process:** regulation of heart rate, intracellular protein localization, positive regulation of neuron projection development, peptide biosynthetic process, positive regulation of neuron differentiation, cardiac muscle contraction.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-04.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Kariminejad - Najmabadi Pathology & Genetics Center | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-03-04 |

## Associated conditions {#conditions}

[Duchenne muscular dystrophy](https://sugi.bio/atlas/disease/duchenne-muscular-dystrophy/).

**Reported phenotype names (ClinVar):** Duchenne muscular dystrophy, Duchenne Muscular Dystrophy (DMD), MUSCULAR DYSTROPHY, PSEUDOHYPERTROPHIC PROGRESSIVE, DUCHENNE TYPE.

## Same-residue context {#hotspot}

Residue **3345** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [DMD p.Arg3345Ter](/variant/dmd-p-arg3345ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DMD variant pages (same residue, condition, or type): [DMD p.Arg3345Ter](/variant/dmd-p-arg3345ter), [DMD p.Arg3345Gln](/variant/dmd-p-arg3345gln), [DMD p.Arg3345Gly](/variant/dmd-p-arg3345gly), [DMD p.Arg3345Pro](/variant/dmd-p-arg3345pro), [DMD p.Arg3345=](/variant/dmd-p-arg3345), [DMD p.Ile245fs](/variant/dmd-p-ile245fs), [DMD p.Ala3421delinsPhePhePhePhePhePheXaaXaaXaaXaaPheHisLysAlaSerIleValIleLeuAlaArgSerGlnTer](/variant/dmd-p-ala3421delinsphephephephephephexaaxaaxaaxaaphehislysalase-fcffcea8), [DMD p.Gln1113fs](/variant/dmd-p-gln1113fs).

### 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 3896838). 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.*