# NM_007078.3(LDB3):c.1609del (p.Gln537fs)

https://sugi.bio/variant/ldb3-p-gln537fs

## Summary

**LDB3 p.Gln537fs (c.1609del)** is classified **Conflicting classifications of pathogenicity** in LDB3 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-05-23). Very rare (popmax 0.000593%, nfe); Associated with Cardiovascular phenotype.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs727503129 · 7 submitters · 3 linked conditions · very rare (popmax 0.000593%, nfe)

## 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 7 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.Gln537fs |
| Coding change (HGVS c.) | c.1609del |
| MANE Select transcript | [NM_007078](https://www.ncbi.nlm.nih.gov/nuccore/NM_007078) |
| dbSNP | [rs727503129](https://www.ncbi.nlm.nih.gov/snp/rs727503129/) |
| Variant type | Deletion |
| Location | chr10:86716703-86716703 (GRCh38) |
| ClinVar | [VCV163850](https://www.ncbi.nlm.nih.gov/clinvar/variation/163850/) |

**All HGVS expressions:** `LRG_385:g.53141del`, `LRG_385t1:c.1609del`, `NC_000010.10:g.88476461del`, `NC_000010.11:g.86716704del`, `NG_008876.1:g.53141del`, `NM_001080114.2:c.1279del`, `NM_001171610.2:c.1624del`, `NM_001368064.1:c.1420del`, `NM_001368065.1:c.1420del`, `NM_001368066.1:c.1468del`, `NM_007078.3:c.1609del`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 7.771, GERP 0.826, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.864, pLI 1.5098e-11. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 10 of 14**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 24.2**. 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: **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 **0.000593%** (nfe) · FAF95 0.000247% · FAF99 0.000159% · 7/1,179,956 in the highest group · 7/1,613,478 alleles overall — very rare (popmax 0.000593%, 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}

**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}


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.


### 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 2025-05-23.

**Submitter consensus:** conflicting (6 Uncertain significance, 1 Pathogenic).

**Submission history:** 7 submissions (2013–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-07-26 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-05-23 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Uncertain significance | criteria provided, single submitter | clinical testing | 2013-10-18 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-01-30 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-06-21 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-05-05 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-08-29 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related LDB3 variant pages (same residue, condition, or type): [LDB3 p.Gln537His](/variant/ldb3-p-gln537his), [LDB3 p.Gln537=](/variant/ldb3-p-gln537), [LDB3 c.860-22_860-12del](/variant/ldb3-c-860-minus-22-860-minus-12del), [LDB3 p.Glu483_Ala485del](/variant/ldb3-p-glu483-ala485del), [LDB3 p.Val676fs](/variant/ldb3-p-val676fs), [LDB3 p.Ala434_Pro449del](/variant/ldb3-p-ala434-pro449del), [LDB3 c.1086-247_1231+2del](/variant/ldb3-c-1086-minus-247-1231-plus-2del), [LDB3 p.Ala319fs](/variant/ldb3-p-ala319fs).

### 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 163850). 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.*