CSRP3

Chr 11AD

cysteine and glycine rich protein 3

Also known as: CLP, CMD1M, CMH12, CRP3, MLP

NCBI Gene: 8048 ENSG00000129170 UniProt: P50461 OMIM: 600824

The CSRP3 protein regulates myogenesis as a cofactor for transcription factors, organizes cytosolic structures in cardiomyocytes including Z-line assembly, and directly binds and cross-links actin filaments while anchoring calcineurin for stress-induced signaling. Mutations cause autosomal dominant dilated cardiomyopathy and hypertrophic cardiomyopathy. This gene primarily affects cardiac muscle function and structure.

OMIM ResearchSummary from OMIM, UniProt

This gene encodes a member of the CSRP family of LIM domain proteins, which may be involved in regulatory processes important for development and cellular differentiation. The LIM/double zinc-finger motif found in this protein is found in a group of proteins with critical functions in gene regulation, cell growth, and somatic differentiation. Mutations in this gene are thought to cause heritable forms of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) in humans. Alternatively spliced transcript variants with different 5' UTR, but encoding the same protein, have been found for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 1.312 OMIM phenotypes

Clinical Summary— CSRP3

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Gene-Disease Validity (ClinGen)

hypertrophic cardiomyopathy · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

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

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Some data sources returned errors (1)

trials: TimeoutError: The operation was aborted due to timeout

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.31LOEUF

pLI 0.000

Z-score 0.88

OE 0.70 (0.40–1.31)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.14Z-score

OE missense 1.04 (0.89–1.21)

115 obs / 110.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.70 (0.40–1.31)

0≤0.351.4

Missense OE?1.04 (0.89–1.21)

0≤0.61.4

Synonymous OE?1.32

0≤1.21.6

LoF obs/exp: 7 / 10.0Missense obs/exp: 115 / 110.9Syn Z: -1.66

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCSRP3-related hypertrophic cardiomyopathyLOFAR

definitiveCSRP3-related hypertrophic cardiomyopathyLOFAD

limitedCSRP3-related dilated cardiomyopathyOTHERAD

This gene — mechanism propensity

0.78top 25%

GOF

0.77top 25%

LOF

0.3356th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNThe NCCM phenotype may be aggravated by a common CSRP3 variant in one of the families. Mutant subunits were nonfunctional and exerted dominant-negative effects on wild-type current.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References