CAV3

Chr 3ADDigenic dominant

caveolin 3

Also known as: LGMD1C, LQT9, MPDT, RMD2, VIP-21, VIP21

NCBI Gene: 859 ENSG00000182533 UniProt: P56539 OMIM: 601253

The protein functions as a scaffolding protein within caveolar membranes, directly interacting with G-protein alpha subunits to regulate their activity and facilitating sarcolemma repair in skeletal muscle and cardiomyocytes. Mutations cause autosomal dominant muscular dystrophies including limb-girdle muscular dystrophy type 1C, rippling muscle disease, distal myopathy, as well as cardiomyopathy and long QT syndrome. Disease predominantly occurs through gain-of-function or dominant-negative mechanisms that disrupt protein oligomerization and caveolae formation.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a caveolin family member, which functions as a component of the caveolae plasma membranes found in most cell types. Caveolin proteins are proposed to be scaffolding proteins for organizing and concentrating certain caveolin-interacting molecules. Mutations identified in this gene lead to interference with protein oligomerization or intra-cellular routing, disrupting caveolae formation and resulting in Limb-Girdle muscular dystrophy type-1C (LGMD-1C), hyperCKemia or rippling muscle disease (RMD). Alternative splicing has been identified for this locus, with inclusion or exclusion of a differentially spliced intron. In addition, transcripts utilize multiple polyA sites and contain two potential translation initiation sites. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/Digenic dominantLOEUF 1.475 OMIM phenotypes

Clinical Summary— CAV3

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Gene-Disease Validity (ClinGen)

long QT syndrome · ADLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

30 unique Pathogenic / Likely Pathogenic· 174 VUS of 418 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — CAV3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.47LOEUF

pLI 0.005

Z-score 0.79

OE 0.66 (0.32–1.47)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.83Z-score

OE missense 0.76 (0.62–0.92)

69 obs / 91.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.66 (0.32–1.47)

0≤0.351.4

Missense OE?0.76 (0.62–0.92)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 4 / 6.1Missense obs/exp: 69 / 91.3Syn Z: -0.58

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedCAV3-related long QT syndromeOTHERAD

This gene — mechanism propensity

0.77top 25%

GOF

0.85top 5%

LOF

0.2288th %ile

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

GOFprediction above median · 1 literature citation

DNprediction above median · 1 literature citation

LOF1 literature citation · 27% of P/LP variants are LoF

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 novel sporadic missense mutation in the caveolin signature sequence of the caveolin-3 gene changes an alanine to a threonine (A46T) and prevents the localization of caveolin-3 to the plasma membrane in a dominant negative fashion.1

GOFWe recently established CAV3-encoded caveolin-3 as a novel LQTS-associated gene with mutations producing a gain-of-function, LQT3-like molecular/cellular phenotype.2

LOFWe used in vivo and in vitro studies to determine the effect of palmitate exposure on global insulin resistance, contractile performance of the heart in vivo, glucose uptake in the heart, and on cellular signaling downstream of theIR We show that haploinsufficiency for CAV3 increases susceptibility 3

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

418 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19

Likely Pathogenic11

VUS174

Likely Benign116

Benign42

Conflicting34

Pathogenic

Likely Pathogenic

174

VUS

116

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	5	10	4	0	19
Likely Pathogenic	3	8	0	0	11
VUS	7	147	20	0	174
Likely Benign	0	3	39	74	116
Benign	0	0	42	0	42
Conflicting	—				34
Total	15	168	105	74	396

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

View in ClinVar →

53 pathogenic / likely-pathogenic (of 68) ClinVar copy-number / structural variants overlap CAV3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →