ClinVar Genomic variation as it relates to human health

Ptosis (present) , Cataract (present) , Stroke disorder (present) , Muscle weakness (present) , Muscular atrophy (present) , Myalgia (present) , Fatigable weakness (present) , Skeletal muscle hypertrophy (present) , Abnormal muscle physiology (present) , Abnormal skeletal muscle morphology (present) , Fatty replacement of skeletal muscle (present) , Highly elevated creatine kinase (present) , Muscle fiber atrophy (present) (less)

The numbering of this CAV3 mutation (R27Q) is based on the numbering system used by Fulizio et al. (2005). Early reports designated this mutation ARG26GLN. In kindred B with autosomal dominant rippling muscle disease (RMD2; 606072) described by Vorgerd et al. (1999), Betz et al. (2001) identified an arg26-to-gln (R26Q) substitution in the CAV3 gene. In a patient with sporadic rippling muscle disease, Vorgerd et al. (2001) identified a heterozygous R26Q mutation in exon 1 of the CAV3 gene, which was not found in either parent. Muscle biopsy of the patient showed reduced sarcolemmal caveolin-3 with punctated cytosolic staining, consistent with intracellular retention of an unstable protein. Neuronal nitric oxide synthase (nNOS) expression was normal. Vorgerd et al. (2001) suggested that increased inducibility of nNOS, caused by lack of inhibition by normal caveolin, may contribute to muscle hyperexcitability in rippling muscle disease. In a 71-year-old woman with a diagnosis of limb-girdle muscular dystrophy (LGMD1C), which was reclassified by Straub et al. (2018) as rippling muscle disease (RMD2; 606072), Figarella-Branger et al. (2003) identified a heterozygous R26Q mutation, which they referred to as ARG27GLN. Muscle biopsy showed fibers of various sizes, centrally located nuclei, occasional necrotic and regenerative fibers, decreased dysferlin immunoreactivity, and near absence of caveolin-3. Although this was a late presentation, the authors could not rule out a very slow but myopathic evolution of a putative hyperCKemia in infancy. Figarella-Branger et al. (2003) emphasized the heterogeneous clinical phenotypes that had been reported in association with this CAV3 mutation. Carbone et al. (2000) identified a de novo recurrent sporadic mutation, R26Q, in the CAV3 gene in 2 unrelated children with persistent elevated levels of serum creatine kinase (hyperCKemia; 123320) without muscle weakness. Immunohistochemistry and quantitative immunoblot analysis of caveolin-3 showed reduced expression of the protein in muscle fibers. Carbone et al. (2000) concluded that partial caveolin-3 deficiency should be considered in the differential diagnosis of idiopathic hyperCKemia. In a Japanese woman with a relatively mild nonspecific sporadic distal myopathy (MPDT; 614321), Tateyama et al. (2002) identified the R26Q mutation. Muscle atrophy and weakness was limited to the small muscles of the hands and feet. She also showed increased creatine kinase, myopathic changes on biopsy and EMG, and decreased caveolin-3 and dysferlin (603009) immunoreactivity. Tateyama et al. (2002) noted the unusual clinical phenotype of the patient. Gonzalez-Perez et al. (2009) identified the R27Q mutation in a Spanish family with autosomal dominant inheritance of distal myopathy and increased serum creatine kinase. The proband was a 77-year-old man who had onset in his mid-forties of distal muscle weakness and atrophy, particularly affecting the thenar and hypothenar muscles in both hands, as well as the intrinsic finger muscles. Other features included calf hypertrophy, pes cavus, and percussion-induced rapid contractions, predominantly in distal muscles of upper limbs. He had 4 affected sons, 3 of whom presented in their twenties with increased serum creatine kinase, calf hypertrophy, and pes cavus; 1 had percussion-induced rapid contractions. All later developed distal muscle weakness and atrophy affecting the hands. The fourth son, aged 33 years, had increased serum creatine kinase and pes cavus, but no evidence of motor deficit. Two granddaughters of the proband had pes cavus and increased serum creatine kinase, but no motor deficit. One had percussion-induced rapid contractions and the other had myalgias. Muscle biopsy of the proband showed slight variation in fiber size and increased number of internal nuclei, but no dystrophic changes. Caveolin-3 expression was greatly reduced in the sarcolemma, and there was a moderate reduction of dysferlin immunolabeling. Electron microscopy revealed focal loss of sarcolemma, abnormal sarcolemmal folding, absence of normal caveolae, and enlarged subsarcolemmal space with large vacuoles. Gonzalez-Perez et al. (2009) noted the variable phenotypic features in this family. (less)

The numbering of this CAV3 mutation (R27Q) is based on the numbering system used by Fulizio et al. (2005). Early reports designated this mutation ARG26GLN. In kindred B with autosomal dominant rippling muscle disease (RMD2; 606072) described by Vorgerd et al. (1999), Betz et al. (2001) identified an arg26-to-gln (R26Q) substitution in the CAV3 gene. In a patient with sporadic rippling muscle disease, Vorgerd et al. (2001) identified a heterozygous R26Q mutation in exon 1 of the CAV3 gene, which was not found in either parent. Muscle biopsy of the patient showed reduced sarcolemmal caveolin-3 with punctated cytosolic staining, consistent with intracellular retention of an unstable protein. Neuronal nitric oxide synthase (nNOS) expression was normal. Vorgerd et al. (2001) suggested that increased inducibility of nNOS, caused by lack of inhibition by normal caveolin, may contribute to muscle hyperexcitability in rippling muscle disease. In a 71-year-old woman with a diagnosis of limb-girdle muscular dystrophy (LGMD1C), which was reclassified by Straub et al. (2018) as rippling muscle disease (RMD2; 606072), Figarella-Branger et al. (2003) identified a heterozygous R26Q mutation, which they referred to as ARG27GLN. Muscle biopsy showed fibers of various sizes, centrally located nuclei, occasional necrotic and regenerative fibers, decreased dysferlin immunoreactivity, and near absence of caveolin-3. Although this was a late presentation, the authors could not rule out a very slow but myopathic evolution of a putative hyperCKemia in infancy. Figarella-Branger et al. (2003) emphasized the heterogeneous clinical phenotypes that had been reported in association with this CAV3 mutation. Carbone et al. (2000) identified a de novo recurrent sporadic mutation, R26Q, in the CAV3 gene in 2 unrelated children with persistent elevated levels of serum creatine kinase (hyperCKemia; 123320) without muscle weakness. Immunohistochemistry and quantitative immunoblot analysis of caveolin-3 showed reduced expression of the protein in muscle fibers. Carbone et al. (2000) concluded that partial caveolin-3 deficiency should be considered in the differential diagnosis of idiopathic hyperCKemia. In a Japanese woman with a relatively mild nonspecific sporadic distal myopathy (MPDT; 614321), Tateyama et al. (2002) identified the R26Q mutation. Muscle atrophy and weakness was limited to the small muscles of the hands and feet. She also showed increased creatine kinase, myopathic changes on biopsy and EMG, and decreased caveolin-3 and dysferlin (603009) immunoreactivity. Tateyama et al. (2002) noted the unusual clinical phenotype of the patient. Gonzalez-Perez et al. (2009) identified the R27Q mutation in a Spanish family with autosomal dominant inheritance of distal myopathy and increased serum creatine kinase. The proband was a 77-year-old man who had onset in his mid-forties of distal muscle weakness and atrophy, particularly affecting the thenar and hypothenar muscles in both hands, as well as the intrinsic finger muscles. Other features included calf hypertrophy, pes cavus, and percussion-induced rapid contractions, predominantly in distal muscles of upper limbs. He had 4 affected sons, 3 of whom presented in their twenties with increased serum creatine kinase, calf hypertrophy, and pes cavus; 1 had percussion-induced rapid contractions. All later developed distal muscle weakness and atrophy affecting the hands. The fourth son, aged 33 years, had increased serum creatine kinase and pes cavus, but no evidence of motor deficit. Two granddaughters of the proband had pes cavus and increased serum creatine kinase, but no motor deficit. One had percussion-induced rapid contractions and the other had myalgias. Muscle biopsy of the proband showed slight variation in fiber size and increased number of internal nuclei, but no dystrophic changes. Caveolin-3 expression was greatly reduced in the sarcolemma, and there was a moderate reduction of dysferlin immunolabeling. Electron microscopy revealed focal loss of sarcolemma, abnormal sarcolemmal folding, absence of normal caveolae, and enlarged subsarcolemmal space with large vacuoles. Gonzalez-Perez et al. (2009) noted the variable phenotypic features in this family. (less)

The numbering of this CAV3 mutation (R27Q) is based on the numbering system used by Fulizio et al. (2005). Early reports designated this mutation ARG26GLN. In kindred B with autosomal dominant rippling muscle disease (RMD2; 606072) described by Vorgerd et al. (1999), Betz et al. (2001) identified an arg26-to-gln (R26Q) substitution in the CAV3 gene. In a patient with sporadic rippling muscle disease, Vorgerd et al. (2001) identified a heterozygous R26Q mutation in exon 1 of the CAV3 gene, which was not found in either parent. Muscle biopsy of the patient showed reduced sarcolemmal caveolin-3 with punctated cytosolic staining, consistent with intracellular retention of an unstable protein. Neuronal nitric oxide synthase (nNOS) expression was normal. Vorgerd et al. (2001) suggested that increased inducibility of nNOS, caused by lack of inhibition by normal caveolin, may contribute to muscle hyperexcitability in rippling muscle disease. In a 71-year-old woman with a diagnosis of limb-girdle muscular dystrophy (LGMD1C), which was reclassified by Straub et al. (2018) as rippling muscle disease (RMD2; 606072), Figarella-Branger et al. (2003) identified a heterozygous R26Q mutation, which they referred to as ARG27GLN. Muscle biopsy showed fibers of various sizes, centrally located nuclei, occasional necrotic and regenerative fibers, decreased dysferlin immunoreactivity, and near absence of caveolin-3. Although this was a late presentation, the authors could not rule out a very slow but myopathic evolution of a putative hyperCKemia in infancy. Figarella-Branger et al. (2003) emphasized the heterogeneous clinical phenotypes that had been reported in association with this CAV3 mutation. Carbone et al. (2000) identified a de novo recurrent sporadic mutation, R26Q, in the CAV3 gene in 2 unrelated children with persistent elevated levels of serum creatine kinase (hyperCKemia; 123320) without muscle weakness. Immunohistochemistry and quantitative immunoblot analysis of caveolin-3 showed reduced expression of the protein in muscle fibers. Carbone et al. (2000) concluded that partial caveolin-3 deficiency should be considered in the differential diagnosis of idiopathic hyperCKemia. In a Japanese woman with a relatively mild nonspecific sporadic distal myopathy (MPDT; 614321), Tateyama et al. (2002) identified the R26Q mutation. Muscle atrophy and weakness was limited to the small muscles of the hands and feet. She also showed increased creatine kinase, myopathic changes on biopsy and EMG, and decreased caveolin-3 and dysferlin (603009) immunoreactivity. Tateyama et al. (2002) noted the unusual clinical phenotype of the patient. Gonzalez-Perez et al. (2009) identified the R27Q mutation in a Spanish family with autosomal dominant inheritance of distal myopathy and increased serum creatine kinase. The proband was a 77-year-old man who had onset in his mid-forties of distal muscle weakness and atrophy, particularly affecting the thenar and hypothenar muscles in both hands, as well as the intrinsic finger muscles. Other features included calf hypertrophy, pes cavus, and percussion-induced rapid contractions, predominantly in distal muscles of upper limbs. He had 4 affected sons, 3 of whom presented in their twenties with increased serum creatine kinase, calf hypertrophy, and pes cavus; 1 had percussion-induced rapid contractions. All later developed distal muscle weakness and atrophy affecting the hands. The fourth son, aged 33 years, had increased serum creatine kinase and pes cavus, but no evidence of motor deficit. Two granddaughters of the proband had pes cavus and increased serum creatine kinase, but no motor deficit. One had percussion-induced rapid contractions and the other had myalgias. Muscle biopsy of the proband showed slight variation in fiber size and increased number of internal nuclei, but no dystrophic changes. Caveolin-3 expression was greatly reduced in the sarcolemma, and there was a moderate reduction of dysferlin immunolabeling. Electron microscopy revealed focal loss of sarcolemma, abnormal sarcolemmal folding, absence of normal caveolae, and enlarged subsarcolemmal space with large vacuoles. Gonzalez-Perez et al. (2009) noted the variable phenotypic features in this family. (less)