# NM_014000.3(VCL):c.1022G>C (p.Arg341Thr)

https://sugi.bio/variant/vcl-p-arg341thr

## Summary

**VCL p.Arg341Thr (c.1022G>C)** is classified **Uncertain significance** in VCL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-29). AlphaMissense: likely pathogenic (0.5909); Very rare (popmax 8.48e-05%, nfe); Associated with dilated cardiomyopathy 1W.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the VCL gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to dilated cardiomyopathy 1W.

*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 | VCL is a diagnostic-grade gene on 5 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/0015515/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [VCL](https://sugi.bio/atlas/gene/VCL/) |
| Protein change (HGVS p.) | p.Arg341Thr |
| Coding change (HGVS c.) | c.1022G>C |
| MANE Select transcript | [NM_014000](https://www.ncbi.nlm.nih.gov/nuccore/NM_014000) |
| Variant type | single nucleotide variant |
| Location | chr10:74083513-74083513 (GRCh38) |
| ClinVar | [VCV3706839](https://www.ncbi.nlm.nih.gov/clinvar/variation/3706839/) |

**All HGVS expressions:** `LRG_383:g.90400G>C`, `LRG_383t1:c.1022G>C`, `NC_000010.10:g.75843271G>C`, `NC_000010.11:g.74083513G>C`, `NG_008868.1:g.90400G>C`, `NM_003373.4:c.1022G>C`, `NM_014000.3:c.1022G>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.5909)
- REVEL 0.2 (benign-leaning) — differs from AlphaMissense
- SaProt LLR -10.004 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt call this damaging; REVEL does not
- SpliceAI predicts **donor loss** (Δ 0.98) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.782, GERP 2.51, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 34.0**. 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.*
- Regional missense constraint: **o/e 0.82** across the covering region of the MANE Select transcript (74,070,820–74,108,996), spanning 38,176 bp. Chi-square p 3e-08. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.98**, acceptor gain **0.00**, donor gain **0.02**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.98**, acceptor gain **0.00**, donor gain **0.02**.
- Pangolin: Δ**0.81** (loss), gain 0.05 / loss 0.81. 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 **8.48e-05%** (nfe) · 1/1,179,794 in the highest group · 1/1,613,686 alleles overall — very rare (popmax 8.48e-05%, nfe).

*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}

**VCL** population constraint: LOEUF 0.461, pLI 0.99858, missense-Z 4.2503. *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):

- **hypertrophic cardiomyopathy** — Disputed (AD)
- **dilated cardiomyopathy 1W** — Strong (AD)
- **congenital heart disease** — No Known Disease Relationship (UD)

## Protein context {#protein}

Residue **341** lies in the 'n-terminal globular head' region; the '3 x 112 aa tandem repeats' region; a turn.

AlphaFold model confidence (whole protein): pLDDT 86.69, 63% of residues very-high.

**37 experimental structure(s)** (PDB): [1RKC](https://www.rcsb.org/structure/1RKC), [1RKE](https://www.rcsb.org/structure/1RKE), [1SYQ](https://www.rcsb.org/structure/1SYQ), [1TR2](https://www.rcsb.org/structure/1TR2), [1YDI](https://www.rcsb.org/structure/1YDI), [2GWW](https://www.rcsb.org/structure/2GWW) — incl. mutant structure 3VF0.

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

*Describes the biological roles of VCL (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:** VCL's established molecular role includes dystroglycan binding. p.Arg341Thr falls in the n-terminal globular head region. In Reactome, VCL is annotated in disease pathway(s) including **Paradoxical activation of RAF signaling by kinase inactive BRAF**, **Signaling by ALK fusions and activated point mutants**.

**Disease mechanism (Reactome):** VCL loss or alteration is curated in [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955), [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370), [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952).

### Pathways affected {#pathways}

VCL participates in **15 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955) | curated |
| ⚕ [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370) | curated |
| ⚕ [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952) | curated |
| ⚕ [Signaling by RAF1 mutants](https://reactome.org/content/detail/R-HSA-9656223) | curated |
| ⚕ [Signaling by high-kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802948) | curated |
| ⚕ [Signaling by moderate kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802946) | curated |
| ⚕ [Signaling downstream of RAS mutants](https://reactome.org/content/detail/R-HSA-9649948) | curated |
| [High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells](https://reactome.org/content/detail/R-HSA-9856530) | curated |
| [MAP2K and MAPK activation](https://reactome.org/content/detail/R-HSA-5674135) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |
| [Regulation of CDH1 Function](https://reactome.org/content/detail/R-HSA-9764561) | curated |
| [Smooth Muscle Contraction](https://reactome.org/content/detail/R-HSA-445355) | curated |
| [Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells](https://reactome.org/content/detail/R-HSA-9860927) | curated |
| [Activation of STAT3 by cadherin engagement](https://reactome.org/content/detail/R-HSA-9958825) | electronic |

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

**Molecular function:** dystroglycan binding, actin binding, ubiquitin protein ligase binding, alpha-catenin binding, cadherin binding, molecular adaptor activity.

**Biological process:** morphogenesis of an epithelium, adherens junction assembly, protein localization to cell surface, apical junction assembly, regulation of focal adhesion assembly, epithelial cell-cell adhesion.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-09-29.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-29 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related VCL variant pages (same residue, condition, or type): [VCL c.1176+4G>C](/variant/vcl-c-1176-plus-4g-c), [VCL c.1352+5G>A](/variant/vcl-c-1352-plus-5g-a), [VCL c.1543+1G>T](/variant/vcl-c-1543-plus-1g-t), [VCL c.1543+4A>G](/variant/vcl-c-1543-plus-4a-g), [VCL c.1743+6A>G](/variant/vcl-c-1743-plus-6a-g), [VCL c.1744-1G>T](/variant/vcl-c-1744-minus-1g-t), [VCL c.2022+5G>T](/variant/vcl-c-2022-plus-5g-t), [VCL c.2023-1G>C](/variant/vcl-c-2023-minus-1g-c).

### 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 3706839). 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.*