# NM_006073.4(TRDN):c.1671A>G (p.Pro557=)

https://sugi.bio/variant/trdn-p-pro557

## Summary

**TRDN p.Pro557= (c.1671A>G)** is classified **Uncertain significance** in TRDN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-12-09). Very rare (popmax 0.00387%, nfe); Associated with catecholaminergic polymorphic ventricular tachycardia 5.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs935484433 · 2 submitters · 2 linked conditions · very rare (popmax 0.00387%, nfe)

## For patients & families {#patients}

This is a change in the TRDN gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to catecholaminergic polymorphic ventricular tachycardia 5.

*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 dominant, Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | 1-5 / 10 000 (Europe) |
| Diagnostic panels | TRDN is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Catecholaminergic polymorphic ventricular tachycardia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Ventricular tachycardia — Very frequent (99-80%)
- Cardiac arrest — Frequent (79-30%)
- Palpitations — Frequent (79-30%)
- Vertigo — Frequent (79-30%)
- Supraventricular tachycardia — Frequent (79-30%)
- Atrial fibrillation — Frequent (79-30%)
- Polymorphic ventricular tachycardia — Frequent (79-30%)
- Syncope — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015967/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TRDN](https://sugi.bio/atlas/gene/TRDN/) |
| Protein change (HGVS p.) | p.Pro557= |
| Coding change (HGVS c.) | c.1671A>G |
| MANE Select transcript | [NM_006073](https://www.ncbi.nlm.nih.gov/nuccore/NM_006073) |
| dbSNP | [rs935484433](https://www.ncbi.nlm.nih.gov/snp/rs935484433/) |
| Variant type | single nucleotide variant |
| Location | chr6:123272965-123272965 (GRCh38) |
| ClinVar | [VCV1032405](https://www.ncbi.nlm.nih.gov/clinvar/variation/1032405/) |

**All HGVS expressions:** `NC_000006.11:g.123594110T>C`, `NC_000006.12:g.123272965T>C`, `NG_030438.1:g.369129A>G`, `NM_006073.4:c.1671A>G`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.74) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.811, GERP 0.787, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 19.27**. 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 deltas (raw): acceptor loss **0.48**, donor loss **0.74**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 1 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.55** (loss), gain 0.01 / loss 0.55. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00387%** (nfe) · FAF95 0.00293% · FAF99 0.00261% · 44/1,137,270 in the highest group · 50/1,528,166 alleles overall — very rare (popmax 0.00387%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0101% | 9,861 |
| European (non-Finnish) (grpmax) | 0.00387% | 25,847 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**TRDN** population constraint: LOEUF 1.359, pLI 1.1258e-24, missense-Z -1.0725; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/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):

- **long QT syndrome** — Strong (AR)
- **catecholaminergic polymorphic ventricular tachycardia** — Definitive (AR)

## Protein context {#protein}

Residue **557** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 47.65, 2% of residues very-high.

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

*Describes the biological roles of TRDN (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.*


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Ion homeostasis](https://reactome.org/content/detail/R-HSA-5578775) | curated |
| [Stimuli-sensing channels](https://reactome.org/content/detail/R-HSA-2672351) | curated |

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

**Biological process:** heart contraction.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2021-12-09.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2018–2021); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-03-02 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-12-09 |

## Associated conditions {#conditions}

[catecholaminergic polymorphic ventricular tachycardia 5](https://sugi.bio/atlas/disease/catecholaminergic-polymorphic-ventricular-tachycardia-5/), [catecholaminergic polymorphic ventricular tachycardia 1](https://sugi.bio/atlas/disease/catecholaminergic-polymorphic-ventricular-tachycardia-1/).

**Reported phenotype names (ClinVar):** Catecholaminergic polymorphic ventricular tachycardia 5, Catecholaminergic polymorphic ventricular tachycardia 1, Ventricular tachycardia, catecholaminergic polymorphic, 5, with or without muscle weakness, CARDIAC ARRHYTHMIA SYNDROME, WITH OR WITHOUT SKELETAL MUSCLE WEAKNESS, RYR2-Related Catecholaminergic Polymorphic Ventricular Tachycardia, VENTRICULAR TACHYCARDIA, STRESS-INDUCED POLYMORPHIC 1, VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1, WITH OR WITHOUT ATRIAL DYSFUNCTION AND/OR DILATED CARDIOMYOPATHY.

## Similar variants {#similar}

Related TRDN variant pages (same residue, condition, or type): [TRDN p.Pro557Gln](/variant/trdn-p-pro557gln), [TRDN c.22+1G>T](/variant/trdn-c-22-plus-1g-t), [TRDN c.22+29A>G](/variant/trdn-c-22-plus-29a-g), [TRDN c.391+1G>A](/variant/trdn-c-391-plus-1g-a), [TRDN p.Gln205Ter](/variant/trdn-p-gln205ter), [TRDN p.Glu168Ter](/variant/trdn-p-glu168ter), [TRDN p.Glu181Ter](/variant/trdn-p-glu181ter), [TRDN p.Lys177Ter](/variant/trdn-p-lys177ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1032405). 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.*