# NM_007078.3(LDB3):c.2091C>T (p.Cys697=)

https://sugi.bio/variant/ldb3-p-cys697

## Summary

**LDB3 p.Cys697= (c.2091C>T)** is classified **Benign/Likely benign** in LDB3 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2025-10-22). Rare (popmax 0.166%, mid); Associated with Cardiovascular phenotype.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs571356142 · 10 submitters · 2 linked conditions · rare (popmax 0.166%, mid)

## For patients & families {#patients}

This is a change in the LDB3 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 10 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 | [LDB3](https://sugi.bio/atlas/gene/LDB3/) |
| Protein change (HGVS p.) | p.Cys697= |
| Coding change (HGVS c.) | c.2091C>T |
| MANE Select transcript | [NM_007078](https://www.ncbi.nlm.nih.gov/nuccore/NM_007078) |
| dbSNP | [rs571356142](https://www.ncbi.nlm.nih.gov/snp/rs571356142/) |
| Variant type | single nucleotide variant |
| Location | chr10:86726249-86726249 (GRCh38) |
| ClinVar | [VCV179942](https://www.ncbi.nlm.nih.gov/clinvar/variation/179942/) |

**All HGVS expressions:** `LRG_385:g.62686C>T`, `LRG_385t1:c.2091C>T`, `NC_000010.10:g.88486006C>T`, `NC_000010.11:g.86726249C>T`, `NG_008876.1:g.62686C>T`, `NM_001080114.2:c.1761C>T`, `NM_001171610.2:c.2106C>T`, `NM_001368064.1:c.1902C>T`, `NM_001368065.1:c.1902C>T`, `NM_001368066.1:c.1950C>T`, `NM_007078.3:c.2091C>T`

## 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 0.20) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -3.418, GERP -4.61 — fast-evolving / accelerated position
- CADD: **PHRED 5.507**. 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 **0.00**, donor loss **0.20**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.20**, acceptor gain **0.00**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.166%** (mid) · FAF95 0.0944% · FAF99 0.0878% · 10/6,014 in the highest group · 159/1,612,932 alleles overall — rare (popmax 0.166%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.166% | 601 |
| South Asian | 0.112% | 893 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,617 |
| East Asian | 0.00446% | 22,436 |
| European (non-Finnish) | 0.00348% | 28,756 |

*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 **697** lies in a UniProt-annotated variant site (in cmd2l; likely pathogenic); the lim zinc-binding 3 domain.

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.Cys697= falls in the lim zinc-binding 3 domain.


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

**Molecular function:** cytoskeletal protein binding.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-22.

**Submitter consensus:** conflicting (8 Likely benign, 2 Benign).

**Submission history:** 10 submissions (2015–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely benign | criteria provided, single submitter | clinical testing | 2015-03-12 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2022-03-19 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-03-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-10-22 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-08-01 |
| Clinical Genetics, Academic Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Likely benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2021-09-08 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related LDB3 variant pages (same residue, condition, or type): [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), [LDB3 c.859+3G>A](/variant/ldb3-c-859-plus-3g-a), [LDB3 c.859+5G>C](/variant/ldb3-c-859-plus-5g-c).

### 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 179942). 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.*