Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies

Gene: CAV3

Green List (high evidence)

Comment on mode of inheritance: There are more than 3 unrelated individuals reported in literature with biallelic CAV3 variants and a caveolinopathy, which primarily manifests in exercise intolerance and elevated CK. Proximal weakness and hypertrophy of limbs are also often reported, though the disease is often mild and slow progressing. The severity of disease does not clearly correlate with the mode of inheritance. Based on available evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.

Created: 6 Aug 2026, 3:03 p.m. | Last Modified: 6 Aug 2026, 3:03 p.m.

Panel Version: 6.17

PMID: 37166430 Berling et al., 2023
Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients.
2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7:
P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance.
P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4).
However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13).

PMID: 18253147 Traverso et al., 2008
Patient 1, a 58yo female, affected by dilated cardiomyopathy and limb girdle muscular dystrophy (LGMD)-1C, showed an autosomal recessive mutation CAV3 c.233C>T, p.(T78M). Neurological examination revealed generalized hypotonia, proximal weakness and hypotrophy of the upper limbs, and proximal hypotrophy and calf hypetrophy of the lower limbs.
Variant has MAF = 0.008413 in gnomAD, including one homozygote - VUS leaning Benign.
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BIALLELIC CASES - review by Ivone Leong, copied from Rhabdomyolysis and metabolic muscle disorders panel

PMID: 9536092, reported one patient with homozygous G56S. The patient was the only member of the family to be affected by disease (proximal muscle weakness in the first decade of life). The variant was not found in 200 controls. The patient's skeletal muscle biopsy looked normal and expression of dystrophin, sarcoglycans and caveolin-3 was normal. This variant was later reclassified as a VUS as PMID:11251997 identified 2 Brazilian patients with LGMD with heterozygous G55S. Both patients had onset in adulthood, calf hypertrophy, elevated creatine kinase, and difficulty walking. Muscle protein analyses from both patients were normal. Screening 200 normal controls showed 4 controls also had this variant.
In OMIM: "Hamosh (2018) found that the G55S variant was present in heterozygous state in 3,142 of 277,064 alleles and in 184 homozygotes in the gnomAD database (January 24, 2018), calling into question the pathogenicity of the variant."

PMID: 12666119, reported an Italian patient with severe rippling muscle disease (A92T) who was AR. Actually A93T.

PMID: 15668980, the same authors of PMID: 12666119 reported 1 family with 2 affected sibs who have AR rippling muscle disease (same variant as above A92T). Unaffected parents were both heterozygous for the variant. The authors note that the parents were not known to be consanguineous but they are from the same small village in Germany. The authors also did a haplotype analysis and showed that this variant arose separately from the Italian case, suggesting that A92 might be a mutation hot spot. According to ClinVar, this variant has conflicting interpretations of pathogenicity (https://www.ncbi.nlm.nih.gov/clinvar/variation/8285/)

PMID: 16730439, reports on 1 patient (AR) with mild proximal muscle weakness of the lower limbs. No other family members were available for further analysis. Patient is homozygous for a splice variant (IVS1+2T>C).
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CAV3 is only associated with autosomal dominant disease entities in OMIM (Cardiomyopathy, familial hypertrophic, MIM:192600; Creatine phosphokinase, elevated serum, MIM:123320; Myopathy, distal, Tateyama type, MIM:614321; Rippling muscle disease 2, MIM:606072; Long QT syndrome 9, MIM:611818). The association between CAV3 and AD caveolinopathy (MONDO:0016146) was classified as Definitive in ClinGen (Muscular Dystrophies and Myopathies GCEP, Sept 2022). Resources accessed 6th Aug 2026).

Created: 6 Aug 2026, 2:45 p.m. | Last Modified: 6 Aug 2026, 2:53 p.m.

Panel Version: 6.15

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
caveolinopathy MONDO:0016146; Myopathy, distal, Tateyama type, OMIM:614321; Rippling muscle disease 2, OMIM:606072; rippling muscle disease 2, MONDO:0019947; distal myopathy, Tateyama type, MONDO:0013686

Publications

• 9536092
• 12666119
• 15668980
• 16730439
• 18253147
• 37166430

Previously: Limb-Girdle Muscular Dystrophy, Dominant;Muscular dystrophy, limb-girdle, type IC, 607801;Rippling muscle disease, 606072;Creatine phosphokinase, elevated serum, 123320;Myopathy, distal, Tateyama type, 614321;Cardiomyopathy, familial hypertrophic, 192600; Limb-girdle muscular dystrophy

Created: 6 Oct 2021, 1:12 p.m. | Last Modified: 6 Oct 2021, 1:12 p.m.

Panel Version: 2.29

Green List (high evidence)

Listed as associated with Limb Girdle Muscular Dystrophy by Gene Advisor (June 2016), Steve Abbs

Created: 27 Jul 2016, 8:21 a.m.