Rhabdomyolysis and metabolic muscle disorders

Gene: CAV3

The mode of inheritance of this gene has been updated to 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' following NHS Genomic Medicine Service approval.

Created: 1 Feb 2023, 2:55 p.m. | Last Modified: 1 Feb 2023, 2:55 p.m.

Panel Version: 2.5

MOI should be changed from "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" to "MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown".

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).

While there are cases of biallelic variants causing disease there are currently no new cases reporting of this (newest report was in 2006). There is currently not enough evidence to support biallelic cause of disease, I suggest changing the MOI to Monoallelic until more evidence is available.

Created: 6 Oct 2021, 2 p.m. | Last Modified: 6 Oct 2021, 2 p.m.

Panel Version: 1.56

Comment on phenotypes: Previously:
Muscular dystrophy, limb-girdle, type IC 607801;Myopathy, distal, Tateyama type 614321;Rippling muscle disease 606072

Created: 15 Jul 2021, 10:41 a.m. | Last Modified: 15 Jul 2021, 10:41 a.m.

Panel Version: 1.48

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

• 15668980
• 12666119
• 9536092
• 11251997
• 16730439

Comment when marking as ready: Associated with phenotype in OMIM, not in G2P / DD. At least 13 variants reported

Created: 4 Jan 2017, 12:20 p.m.

Comment on phenotypes: Also associated with Cardiomyopathy, familial hypertrophic 192600; Creatine phosphokinase, elevated serum 123320; Long QT syndrome 9 611818;

Created: 4 Jan 2017, 12:13 p.m.

Comment on mode of inheritance: Both monoallelic and biallelic for Muscular dystrophy, limb-girdle, type IC 607801, monoallelic for Myopathy, distal, Tateyama type 614321 and Rippling muscle disease 606072

Created: 4 Jan 2017, 12:13 p.m.

Green List (high evidence)

Phenotypes
muscle cramps and rhabdomyolysis phenotype