# NM_001267550.2(TTN):c.1933_1935del (p.Glu645del)

https://sugi.bio/variant/ttn-p-glu645del

## Summary

**TTN p.Glu645del (c.1933_1935del)** is classified **Uncertain significance** in TTN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-12). Ultra-rare (popmax 0.0217%, amr); Associated with Cardiovascular phenotype.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs774138200 · 3 submitters · 1 linked condition · ultra-rare (popmax 0.0217%, amr)

## For patients & families {#patients}

This is a change in the TTN gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to Cardiovascular phenotype.

*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.*

**Support & next steps:** [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.Glu645del |
| Coding change (HGVS c.) | c.1933_1935del |
| MANE Select transcript | [NM_001267550](https://www.ncbi.nlm.nih.gov/nuccore/NM_001267550) |
| dbSNP | [rs774138200](https://www.ncbi.nlm.nih.gov/snp/rs774138200/) |
| Variant type | Deletion |
| Location | chr2:178789981-178789983 (GRCh38) |
| ClinVar | [VCV426953](https://www.ncbi.nlm.nih.gov/clinvar/variation/426953/) |

**All HGVS expressions:** `LRG_391:g.45820_45822del`, `LRG_391t1:c.1933_1935del`, `NC_000002.11:g.179654710_179654712del`, `NC_000002.12:g.178789983_178789985del`, `NG_011618.3:g.45820_45822del`, `NM_001256850.1:c.1933_1935del`, `NM_001256850.1:c.1933_1935delGAG`, `NM_001267550.1:c.1933_1935del`, `NM_001267550.2:c.1933_1935del`, `NM_003319.4:c.1795_1797del`, `NM_003319.4:c.1795_1797delGAG`, `NM_133378.4:c.1933_1935del`, `NM_133378.4:c.1933_1935delGAG`, `NM_133379.5:c.1933_1935del`, `NM_133432.3:c.1795_1797del`, `NM_133437.4:c.1795_1797del`

## 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 6.217, GERP 2.3, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **in-frame indel**.
- CADD: **PHRED 17.79**. 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: **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 (gnomAD v4.1): grpmax **0.0217%** (amr) · FAF95 0.0127% · FAF99 0.0101% · 13/59,982 in the highest group · 13/1,612,778 alleles overall — ultra-rare (popmax 0.0217%, amr).

*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 2/3, triplosensitivity 0/3. *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}


**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.


### 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-12.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2024–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-23 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-01-12 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-10 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, not provided, not specified, none provided, AllHighlyPenetrant.

## Similar variants {#similar}

Related TTN variant pages (same residue, condition, or type): [TTN p.Glu645=](/variant/ttn-p-glu645), [TTN c.80003_80028+4del](/variant/ttn-c-80003-80028-plus-4del), [TTN p.Ala18143fs](/variant/ttn-p-ala18143fs), [TTN p.Ala24870fs](/variant/ttn-p-ala24870fs), [TTN p.Ala29119fs](/variant/ttn-p-ala29119fs), [TTN p.Arg13741fs](/variant/ttn-p-arg13741fs), [TTN p.Arg14079fs](/variant/ttn-p-arg14079fs), [TTN p.Arg27948fs](/variant/ttn-p-arg27948fs).

### 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 2026-10-14); 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 426953). 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.*