LDB3

Chr 10ADAR

LIM domain binding 3

Also known as: CMD1C, CMD2L, CMH24, CMPD3, CYPHER, LDB3Z1, LDB3Z4, LVNC3

NCBI Gene: 11155 ENSG00000122367 UniProt: O75112

This gene encodes a PDZ domain-containing protein. PDZ motifs are modular protein-protein interaction domains consisting of 80-120 amino acid residues. PDZ domain-containing proteins interact with each other in cytoskeletal assembly or with other proteins involved in targeting and clustering of membrane proteins. The protein encoded by this gene interacts with alpha-actinin-2 through its N-terminal PDZ domain and with protein kinase C via its C-terminal LIM domains. The LIM domain is a cysteine-rich motif defined by 50-60 amino acids containing two zinc-binding modules. This protein also interacts with all three members of the myozenin family. Mutations in this gene have been associated with myofibrillar myopathy and dilated cardiomyopathy. Alternatively spliced transcript variants encoding different isoforms have been identified; all isoforms have N-terminal PDZ domains while only longer isoforms (1, 2 and 5) have C-terminal LIM domains. [provided by RefSeq, Jan 2010]

Primary Disease Associations & Inheritance

Cardiomyopathy, dilated, 1C, with or without LVNCMIM #601493

Cardiomyopathy, dilated, 2LMIM #621237

Cardiomyopathy, hypertrophic, 24MIM #601493

Left ventricular noncompaction 3MIM #601493

Myopathy, myofibrillar, 4MIM #609452

UniProtCardiomyopathy, familial hypertrophic, 24

1642

ClinVar variants

Pathogenic / LP

0.00

pLI score

Active trials

Clinical Summary— LDB3

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

20 Pathogenic / Likely Pathogenic· 349 VUS of 1642 total submissions

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.68LOEUF

pLI 0.000

Z-score 2.99

OE 0.43 (0.28–0.68)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

0.29Z-score

OE missense 0.96 (0.89–1.04)

431 obs / 448.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.43 (0.28–0.68)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.96 (0.89–1.04)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.07

0≤1.21.6

LoF obs/exp: 14 / 32.4Missense obs/exp: 431 / 448.1Syn Z: -0.71

ClinVar Variant Classifications

1642 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic16

Likely Pathogenic4

VUS349

Likely Benign113

Benign3

Conflicting10

Pathogenic

Likely Pathogenic

349

VUS

113

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	10	0	6	0	16
Likely Pathogenic	4	0	0	0	4
VUS	13	262	40	34	349
Likely Benign	0	11	33	69	113
Benign	0	0	3	0	3
Conflicting	—				10
Total	27	273	82	103	495

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

LDB3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

LDB3-related dilated cardiomyopathy

limited

ADUndeterminedUncertain

Cardiac

G2P ↗

LDB3-related arrhythmogenic right ventricular cardiomyopathy

disputed

ADUndeterminedUncertain

Cardiac

G2P ↗

LDB3-related myopathy myofibrillar

limited

ADUndeterminedAltered Gene Product Structure

Dev. Disorders

G2P ↗

missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

LIM DOMAIN-BINDING 3; LDB3

MIM #605906 · *

Cardiomyopathy, dilated, 1C, with or without LVNC

MIM #601493