# NM_001267550.2(TTN):c.10062del (p.Val3355fs)

https://sugi.bio/variant/ttn-p-val3355fs

## Summary

**TTN p.Val3355fs (c.10062del)** is classified **Likely pathogenic** in TTN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-17). No gnomAD frequency available for this variant; Associated with autosomal recessive limb-girdle muscular dystrophy type 2J.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1553983844 · 1 submitter · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the TTN gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to autosomal recessive limb-girdle muscular dystrophy type 2J.

*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 |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | TTN is a diagnostic-grade gene on 15 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012534/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TTN](https://sugi.bio/atlas/gene/TTN/) |
| Protein change (HGVS p.) | p.Val3355fs |
| Coding change (HGVS c.) | c.10062del |
| MANE Select transcript | [NM_001267550](https://www.ncbi.nlm.nih.gov/nuccore/NM_001267550) |
| dbSNP | [rs1553983844](https://www.ncbi.nlm.nih.gov/snp/rs1553983844/) |
| Variant type | Deletion |
| Location | chr2:178764229-178764229 (GRCh38) |
| ClinVar | [VCV534999](https://www.ncbi.nlm.nih.gov/clinvar/variation/534999/) |

**All HGVS expressions:** `LRG_391:g.71574del`, `NC_000002.11:g.179628956del`, `NC_000002.12:g.178764229del`, `NG_011618.3:g.71574del`, `NM_001256850.1:c.10062del`, `NM_001267550.2:c.10062del`, `NM_001267550.2:c.10062delT`, `NM_003319.4:c.9924del`, `NM_133378.4:c.10062del`, `NM_133379.5:c.10062del`, `NM_133432.3:c.9924del`, `NM_133437.4:c.9924del`

## 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 0.859, GERP 0.951, phastCons 0.275 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.479, pLI 1.3925e-89. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 43 of 363**, 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}

**TTN** population constraint: LOEUF 0.479, pLI 1.3925e-89, missense-Z 7.0514; ClinGen dosage — haploinsufficiency 2, 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):

- **dilated cardiomyopathy 1G** — Definitive (AD)
- **TTN-related myopathy** — Definitive (AR)
- **arrhythmogenic right ventricular cardiomyopathy** — Disputed (AD)
- **myopathy, myofibrillar, 9, with early respiratory failure** — Definitive (AD)

## Protein context {#protein}

Residue **3355** lies in the ig-like 20 domain.

**64 experimental structure(s)** (PDB): [1BPV](https://www.rcsb.org/structure/1BPV), [1G1C](https://www.rcsb.org/structure/1G1C), [1NCT](https://www.rcsb.org/structure/1NCT), [1NCU](https://www.rcsb.org/structure/1NCU), [1TIT](https://www.rcsb.org/structure/1TIT), [1TIU](https://www.rcsb.org/structure/1TIU) — incl. mutant structure 2RQ8.

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

*Describes the biological roles of TTN (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:** TTN's established molecular role includes protease binding. p.Val3355fs falls in the ig-like 20 domain.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |
| [Striated Muscle Contraction](https://reactome.org/content/detail/R-HSA-390522) | curated |

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

**Molecular function:** protease binding, protein serine/threonine kinase activity, protein tyrosine kinase activity, calcium ion binding, calmodulin binding, structural constituent of muscle.

**Biological process:** cardiac muscle hypertrophy, mitotic chromosome condensation, positive regulation of gene expression, skeletal muscle thin filament assembly, skeletal muscle myosin thick filament assembly, detection of muscle stretch.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-17.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-10-17 |

## Associated conditions {#conditions}

[autosomal recessive limb-girdle muscular dystrophy type 2J](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy-type-2j/), [dilated cardiomyopathy 1G](https://sugi.bio/atlas/disease/dilated-cardiomyopathy-1g/).

**Reported phenotype names (ClinVar):** Autosomal recessive limb-girdle muscular dystrophy type 2J, Dilated cardiomyopathy 1G, Limb-girdle muscular dystrophy, type 2J, MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 10.

## Similar variants {#similar}

Related TTN variant pages (same residue, condition, or type): [TTN p.Val3355=](/variant/ttn-p-val3355), [TTN c.32888-1del](/variant/ttn-c-32888-minus-1del), [TTN c.49648+2del](/variant/ttn-c-49648-plus-2del), [TTN c.80003_80028+4del](/variant/ttn-c-80003-80028-plus-4del), [TTN c.86822-1del](/variant/ttn-c-86822-minus-1del), [TTN p.Ala14213fs](/variant/ttn-p-ala14213fs), [TTN p.Ala18013fs](/variant/ttn-p-ala18013fs), [TTN p.Ala18143fs](/variant/ttn-p-ala18143fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 534999). 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.*