# NM_002667.5(PLN):c.105_106del (p.Phe35fs)

https://sugi.bio/variant/pln-p-phe35fs

## Summary

**PLN p.Phe35fs (c.105_106del)** is classified **Pathogenic** in PLN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-30). Very rare (popmax 0.0011%, sas); Associated with dilated cardiomyopathy 1P.

**At a glance:** Pathogenic · review: Single submitter · rsID rs747947483 · 1 submitter · 1 linked condition · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the PLN gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to dilated cardiomyopathy 1P.

*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, Mitochondrial inheritance |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 100 000 (Europe) |
| Diagnostic panels | PLN is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Familial isolated dilated cardiomyopathy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Dilated cardiomyopathy — Very frequent (99-80%)
- Left ventricular systolic dysfunction — Very frequent (99-80%)
- Edema — Frequent (79-30%)
- Congestive heart failure — Frequent (79-30%)
- Exertional dyspnea — Frequent (79-30%)
- Arrhythmia — Frequent (79-30%)
- Fatigue — Frequent (79-30%)
- Orthopnea — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015469/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PLN](https://sugi.bio/atlas/gene/PLN/) |
| Protein change (HGVS p.) | p.Phe35fs |
| Coding change (HGVS c.) | c.105_106del |
| MANE Select transcript | [NM_002667](https://www.ncbi.nlm.nih.gov/nuccore/NM_002667) |
| dbSNP | [rs747947483](https://www.ncbi.nlm.nih.gov/snp/rs747947483/) |
| Variant type | Deletion |
| Location | chr6:118559025-118559026 (GRCh38) |
| ClinVar | [VCV1977709](https://www.ncbi.nlm.nih.gov/clinvar/variation/1977709/) |

**All HGVS expressions:** `LRG_390:g.15748_15749del`, `LRG_390t1:c.105_106del`, `NC_000006.11:g.118880189_118880190del`, `NC_000006.12:g.118559026_118559027del`, `NG_009082.1:g.15748_15749del`, `NG_021248.1:g.156050_156051del`, `NM_001042475.3:c.1020+6503_1020+6504del`, `NM_001178035.2:c.1029+6503_1029+6504del`, `NM_002667.5:c.105_106del`, `NM_206921.3:c.1020+6503_1020+6504del`

## 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 7.877, GERP 2.17, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.704, pLI 0.41691. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (2 of 2)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- 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 **0.0011%** (sas) · FAF95 2.8e-05% · FAF99 1.1e-05% · 1/91,010 in the highest group · 3/1,458,226 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0011% | 91,010 |
| European (non-Finnish) | 0.00017% | 588,370 |

*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}

**PLN** population constraint: LOEUF 1.704, pLI 0.41691, missense-Z -0.41779; ClinGen dosage — haploinsufficiency 1, 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):

- **arrhythmogenic right ventricular cardiomyopathy** — Moderate (AD)
- **intrinsic cardiomyopathy** — Definitive (AD)

## Protein context {#protein}

Residue **35** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 81.81, 39% of residues very-high.

**7 experimental structure(s)** (PDB): [1PLP](https://www.rcsb.org/structure/1PLP), [1ZLL](https://www.rcsb.org/structure/1ZLL), [2HYN](https://www.rcsb.org/structure/2HYN), [6Y40](https://www.rcsb.org/structure/6Y40), [7E0Z](https://www.rcsb.org/structure/7E0Z), [7E11](https://www.rcsb.org/structure/7E11).

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

*Describes the biological roles of PLN (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:** PLN's established molecular role includes ATPase inhibitor activity.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Ion homeostasis](https://reactome.org/content/detail/R-HSA-5578775) | curated |
| [Ion transport by P-type ATPases](https://reactome.org/content/detail/R-HSA-936837) | curated |

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

**Molecular function:** ATPase inhibitor activity, transmembrane transporter binding, transporter inhibitor activity.

**Biological process:** regulation of heart contraction, negative regulation of heart rate, regulation of cytosolic calcium ion concentration, regulation of calcium ion transport, negative regulation of calcium ion transport, regulation of cardiac muscle cell contraction.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-30.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-05-30 |

## Associated conditions {#conditions}

[dilated cardiomyopathy 1P](https://sugi.bio/atlas/disease/dilated-cardiomyopathy-1p/).

**Reported phenotype names (ClinVar):** Dilated cardiomyopathy 1P.

## Similar variants {#similar}

Related PLN variant pages (same residue, condition, or type): [PLN c.-97-?_*1344+?del](/variant/pln-c-minus-97-minus-star-1344-plus-del), [PLN p.Phe32fs](/variant/pln-p-phe32fs), [PLN p.Val49fs](/variant/pln-p-val49fs), [PLN c.-120C>T](/variant/pln-c-minus-120c-t), [PLN c.-97-5T>C](/variant/pln-c-minus-97-minus-5t-c), [PLN c.*1225C>T](/variant/pln-c-star-1225c-t), [PLN c.*1243C>T](/variant/pln-c-star-1243c-t), [PLN c.*277A>G](/variant/pln-c-star-277a-g).

### 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 1977709). 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.*