ClinVar Genomic variation as it relates to human health

Thumbs, congenital Clasped (present) , Arthrogryposis multiplex congenita (present) , Decreased fetal movement (present) , Elbow flexion contracture (present) , Generalized hypotonia (present) , Hip contracture (present) , Fetal growth restriction (present) , Knee flexion contracture (present) , Trismus (present) , Muscle weakness (present) , Overlapping fingers (present) , Plantar flexion contracture (present) , Respiratory insufficiency (present) , Small for gestational age (present) , Tongue fasciculations (present) , Unilateral microphthalmos (present) , Wrist flexion contracture (present) (less)

Dolichocephaly (present) , Metopic synostosis (present) , Abnormality of the fontanelles or cranial sutures (present) , Sensorineural hearing loss (present) , Atresia of the external auditory canal (present) , Esophageal atresia (present) , Chronic lung disease (present) , Obstructive sleep apnea syndrome (present) , Imperforate anus (present) , Duodenal atresia (disease) (present) , Growth delay (present) , Pelvic kidney (present) , Renal agenesis (present) , Hypospadias, penile (present) , Cryptorchidism (present) , Kyphoscoliosis (present) , Abnormal vertebral morphology (present) , Pectus carinatum (present) , Clubfoot (present) , Flexion contracture (present) , Camptodactyly (present) , Patellar hypoplasia (present) , Limb undergrowth (present) , Tethered cord (present) , Neurogenic bladder (present) , Seizures (present) , Delayed speech and language development (present) , Posteriorly rotated ears (present) , Narrow palate (present) , Dental crowding (present) , Clinodactyly of the 5th finger (present) , Coarctation of aorta (present) , Polyhydramnios (present) , Cerebral palsy (present) (less)

Distal Hereditary Motor Neuropathy 8, Autosomal Dominant In affected members of a large family in which 20 individuals had autosomal dominant distal hereditary motor neuropathy-8 (HMND8; 600175), Auer-Grumbach et al. (2010) identified a heterozygous c.806G-A transition in exon 5 of the TRPV4 gene, resulting in an arg269-to-his (R269H) substitution. The family had originally been reported by Fleury and Hageman (1985). The mutation was not found in 162 European control individuals. The mutation occurred at the outer helices of the ANK4 and ANK5 domains. In vitro functional expression studies in HeLa cells showed that the mutant protein formed cytoplasmic aggregates and had significantly reduced surface expression. In cotransfection studies, both mutant and wildtype proteins were detected in cytoplasmic aggregates. Mutant TRPV4 cells showed an impaired response to stimulus-dependent channel activity. The studies suggested that the mutation interferes with normal channel trafficking and function, which the authors predicted would result in haploinsufficiency. Hereditary Motor and Sensory Neuropathy Type IIC In affected members of the family with hereditary motor and sensory neuropathy type IIC (HMSN2C; 606071) reported by Dyck et al. (1994), Deng et al. (2010) and Landoure et al. (2010) independently identified a heterozygous R269H mutation in the TRPV4 gene. Deng et al. (2010) did not find the mutation in over 700 control samples. Studies in transiently transfected HEK293 cells showed that the mutant protein was expressed at the plasma membrane, suggesting no defect in channel assembly or intracellular trafficking. Functional studies suggested that the mutation resulted in increased constitutive calcium channel activity, both under basal conditions and in response to stimuli, compared to wildtype. Deng et al. (2010) postulated a gain-of-function mechanism. The studies of Landoure et al. (2010) showed that the mutant protein caused cell death in cultured neuronal cells and in HEK293 cells, where cell death was associated with increased intracellular calcium. Further studies in Xenopus oocytes showed that the mutant channel was expressed normally at the cell surface and had increased current activity compared to wildtype. Mutant TRPV4 expressed in HeLa and HEK293 cells showed similar spatial distributions of the channel at the plasma membrane. Another pathogenic mutation was identified in this same codon (R269C; 605427.0011). Variant Function Commenting on the divergent functional findings of Auer-Grumbach et al. (2010) and Deng et al. (2010) and Landoure et al. (2010), Nilius and Owsianik (2010) suggested that the discrepancies were related to differences in experimental protocols. By in vitro functional expression studies, Klein et al. (2011) showed that the mutant R269H protein caused increased agonist-induced channel activity and increased basal intracellular calcium concentrations in HEK293 cells compared to wildtype. HeLa cells expressing the mutant protein showed increased cell death, which could be suppressed by the TRPV antagonist ruthenium red. The findings were consistent with a pathogenic gain of function. (less)

Distal Hereditary Motor Neuropathy 8, Autosomal Dominant In affected members of a large family in which 20 individuals had autosomal dominant distal hereditary motor neuropathy-8 (HMND8; 600175), Auer-Grumbach et al. (2010) identified a heterozygous c.806G-A transition in exon 5 of the TRPV4 gene, resulting in an arg269-to-his (R269H) substitution. The family had originally been reported by Fleury and Hageman (1985). The mutation was not found in 162 European control individuals. The mutation occurred at the outer helices of the ANK4 and ANK5 domains. In vitro functional expression studies in HeLa cells showed that the mutant protein formed cytoplasmic aggregates and had significantly reduced surface expression. In cotransfection studies, both mutant and wildtype proteins were detected in cytoplasmic aggregates. Mutant TRPV4 cells showed an impaired response to stimulus-dependent channel activity. The studies suggested that the mutation interferes with normal channel trafficking and function, which the authors predicted would result in haploinsufficiency. Hereditary Motor and Sensory Neuropathy Type IIC In affected members of the family with hereditary motor and sensory neuropathy type IIC (HMSN2C; 606071) reported by Dyck et al. (1994), Deng et al. (2010) and Landoure et al. (2010) independently identified a heterozygous R269H mutation in the TRPV4 gene. Deng et al. (2010) did not find the mutation in over 700 control samples. Studies in transiently transfected HEK293 cells showed that the mutant protein was expressed at the plasma membrane, suggesting no defect in channel assembly or intracellular trafficking. Functional studies suggested that the mutation resulted in increased constitutive calcium channel activity, both under basal conditions and in response to stimuli, compared to wildtype. Deng et al. (2010) postulated a gain-of-function mechanism. The studies of Landoure et al. (2010) showed that the mutant protein caused cell death in cultured neuronal cells and in HEK293 cells, where cell death was associated with increased intracellular calcium. Further studies in Xenopus oocytes showed that the mutant channel was expressed normally at the cell surface and had increased current activity compared to wildtype. Mutant TRPV4 expressed in HeLa and HEK293 cells showed similar spatial distributions of the channel at the plasma membrane. Another pathogenic mutation was identified in this same codon (R269C; 605427.0011). Variant Function Commenting on the divergent functional findings of Auer-Grumbach et al. (2010) and Deng et al. (2010) and Landoure et al. (2010), Nilius and Owsianik (2010) suggested that the discrepancies were related to differences in experimental protocols. By in vitro functional expression studies, Klein et al. (2011) showed that the mutant R269H protein caused increased agonist-induced channel activity and increased basal intracellular calcium concentrations in HEK293 cells compared to wildtype. HeLa cells expressing the mutant protein showed increased cell death, which could be suppressed by the TRPV antagonist ruthenium red. The findings were consistent with a pathogenic gain of function. (less)