# NM_007078.3(LDB3):c.1799G>C (p.Arg600Pro)

https://sugi.bio/variant/ldb3-p-arg600pro

## Summary

**LDB3 p.Arg600Pro (c.1799G>C)** is classified **Conflicting classifications of pathogenicity** in LDB3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-06-16). AlphaMissense: ambiguous (0.4499); Absent from gnomAD v4.1; Associated with myofibrillar myopathy 4.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs747523570 · 2 submitters · 1 linked condition · AlphaMissense ambiguous · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the LDB3 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to myofibrillar myopathy 4.

*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 |
| Age of onset (of this condition) | Adult |
| Prevalence | <1 / 1 000 000 (Worldwide) |
| Diagnostic panels | LDB3 is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Late-onset distal myopathy, Markesbery-Griggs type** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Intrinsic hand muscle atrophy — Frequent (79-30%)
- Progressive proximal muscle weakness — Frequent (79-30%)
- Fatigable weakness of distal limb muscles — Frequent (79-30%)
- Abnormality of the cardiovascular system — Occasional (29-5%)
- Leg muscle stiffness — Occasional (29-5%)
- Weakness of the intrinsic hand muscles — Occasional (29-5%)
- Weakness of long finger extensor muscles — Occasional (29-5%)
- Wrist drop — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0001886/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [LDB3](https://sugi.bio/atlas/gene/LDB3/) |
| Protein change (HGVS p.) | p.Arg600Pro |
| Coding change (HGVS c.) | c.1799G>C |
| MANE Select transcript | [NM_007078](https://www.ncbi.nlm.nih.gov/nuccore/NM_007078) |
| dbSNP | [rs747523570](https://www.ncbi.nlm.nih.gov/snp/rs747523570/) |
| Variant type | single nucleotide variant |
| Location | chr10:86718086-86718086 (GRCh38) |
| ClinVar | [VCV191006](https://www.ncbi.nlm.nih.gov/clinvar/variation/191006/) |

**All HGVS expressions:** `LRG_385:g.54523G>C`, `NC_000010.10:g.88477843G>C`, `NC_000010.11:g.86718086G>C`, `NG_008876.1:g.54523G>C`, `NM_001080114.2:c.1469G>C`, `NM_001171610.2:c.1814G>C`, `NM_001368064.1:c.1610G>C`, `NM_001368065.1:c.1610G>C`, `NM_001368066.1:c.1658G>C`, `NM_007078.3:c.1799G>C`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL are indeterminate here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.4499) — no call either way
- REVEL 0.608 (indeterminate)
- SaProt LLR -9.225 (tolerated)
- Conservation: phyloP 8.558, GERP 0.174, phastCons 1 — highly conserved
- CADD: **PHRED 25.7**. 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 0.95** across the covering region of the MANE Select transcript (86,668,692–86,732,973), spanning 64,281 bp. Chi-square p 0.14. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>A, Δ0.29 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**LDB3** population constraint: LOEUF 0.864, pLI 1.5098e-11, missense-Z 0.90565. *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 1C** — Limited (AD)
- **arrhythmogenic right ventricular cardiomyopathy** — Disputed (AD)
- **cardiomyopathy, dilated, 2l** — Strong (AR)

## Protein context {#protein}

Residue **600** lies in the lim zinc-binding 1 domain; a UniProt-annotated variant site (in cmd2l; likely pathogenic).

AlphaFold model confidence (whole protein): pLDDT 61.98, 22% of residues very-high.

**2 experimental structure(s)** (PDB): [1RGW](https://www.rcsb.org/structure/1RGW), [4YDP](https://www.rcsb.org/structure/4YDP).

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

*Describes the biological roles of LDB3 (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:** LDB3's established molecular role includes cytoskeletal protein binding. p.Arg600Pro falls in the lim zinc-binding 1 domain.


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

**Molecular function:** cytoskeletal protein binding.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2023-06-16.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Uncertain significance).

**Submission history:** 2 submissions (2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Likely pathogenic | criteria provided, single submitter | research |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-06-16 |

## Associated conditions {#conditions}

[myofibrillar myopathy 4](https://sugi.bio/atlas/disease/myofibrillar-myopathy-4/).

**Reported phenotype names (ClinVar):** Myofibrillar myopathy 4, not provided, none provided, Zaspopathy (type).

## Similar variants {#similar}

Related LDB3 variant pages (same residue, condition, or type): [LDB3 p.Arg600Gln](/variant/ldb3-p-arg600gln), [LDB3 p.Arg600Ter](/variant/ldb3-p-arg600ter), [LDB3 p.Ala147Thr](/variant/ldb3-p-ala147thr), [LDB3 p.Ala165Val](/variant/ldb3-p-ala165val), [LDB3 c.1231+4A>C](/variant/ldb3-c-1231-plus-4a-c), [LDB3 c.1858-11C>A](/variant/ldb3-c-1858-minus-11c-a), [LDB3 c.246-3C>T](/variant/ldb3-c-246-minus-3c-t), [LDB3 c.322-1G>A](/variant/ldb3-c-322-minus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 191006). 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.*