ClinVar Genomic variation as it relates to human health

Abnormal pinna morphology (present) , Abnormal thorax morphology (present) , Arthrogryposis-like hand anomaly (present) , Camptodactyly (present) , Hepatoblastoma (present) , Narrow chest (present) , Paroxysmal atrial tachycardia (present) , Pectus excavatum (present) (less)

Abnormal heart morphology (present) , Multifocal atrial tachycardia (present) , Pleural effusion (present) , Respiratory insufficiency (present) , Respiratory insufficiency (present) , Immunodeficiency (present) , Hypotonia (present) , Global developmental delay (present) , Failure to thrive (present) (less)

Delayed myelination (present) , Downslanted palpebral fissures (present) , Abnormal facial shape (present) , Failure to thrive (present) , Feeding difficulties (present) , Depressed nasal bridge (present) , Frontal bossing (present) , Full cheeks (present) , High, narrow palate (present) , Hypertelorism (present) , Generalized hypotonia (present) , Abnormality of limbs (present) , Low-set ears (present) , Relative macrocephaly (present) , Mild short stature (present) , Short chin (present) , Myopathy (present) , Short stature (present) (less)

Costello Syndrome In 3 Japanese and in 4 Italian patients with Costello syndrome (218040), Aoki et al. (2005) identified a germline 34G-A transition in the HRAS gene that caused a gly12-to-ser (G12S) amino acid substitution. Kerr et al. (2006) analyzed the HRAS gene in 43 patients with a clinical diagnosis of Costello syndrome and identified mutations in 37 (86%); G12S was the most common mutation, found in 30 of the 37 mutation-positive patients. Zampino et al. (2007) identified the G12S mutation in 8 of 9 unrelated patients with Costello syndrome. By analyzing the flanking genomic region, the authors determined that all patients had de novo mutations inherited from the father. There was an advanced age at conception in affected fathers transmitting the mutation. The phenotype was homogeneous. In a male infant with severe Costello syndrome, Lo et al. (2008) identified the G12S mutation in the HRAS gene. The patient had persistent neonatal hypoglycemia, hypocalcemia, right ventricular hypertrophy, and enlarged kidneys. He required pyloromyotomy for pyloric stenosis and inguinal hernia repair at age 3 months. He had complex upper and lower airway obstruction with a floppy tongue, narrow subglottic opening, and tracheobronchomalacia, requiring a tracheostomy with intermittent ventilatory support. Deterioration of his respiratory function led to the discovery of a pulmonary rhabdomyosarcoma, and he died at 2.25 years of age. Congenital Myopathy with Excess of Muscle Spindles Van der Burgt et al. (2007) identified a heterozygous G12S mutation in the HRAS gene in a patient with congenital myopathy with excess of muscle spindles (see 218040), a phenotypic variant of Costello syndrome. The patient, originally reported by Selcen et al. (2001), died at age 14 months of cardiorespiratory failure. He had generalized muscle weakness, areflexia, joint contractures, and clubfeet. Epidermal Nevus and Urothelial Cancer, Somatic Hafner et al. (2011) reported a 49-year-old man who had widespread mosaicism for a G12S mutation present in tissues derived from endoderm, ectoderm, and mesoderm, suggesting an embryonic mutation. The patient presented at 49 years of age with widespread congenital epidermal nevus (162900). At 19 years of age a urothelial cell carcinoma was detected in the bladder, and 2 new tumors were identified at 48 years of age. At age 49 a single metastatic lesion was identified in lung. Nevus Sebaceous, Somatic Groesser et al. (2012) identified a somatic G12S mutation in 3 (5%) of 65 nevus sebaceous tumors (see 162900). Woolly Hair Nevus, Somatic By paired whole-exome sequencing of DNA in affected tissue and blood from 2 unrelated girls with woolly hair nevus (see 162900), Levinsohn et al. (2014) identified heterozygosity for a somatic G12S mutation in the HRAS gene in both individuals. Analysis of hair bulbs from straight and curly patient hair confirmed that the G12S mutation was present in curly hair only. There was no evidence for loss of heterozygosity or a secondary somatic mutation, suggesting that HRAS mutation alone is sufficient to cause woolly hair nevus. (less)

Costello Syndrome In 3 Japanese and in 4 Italian patients with Costello syndrome (218040), Aoki et al. (2005) identified a germline 34G-A transition in the HRAS gene that caused a gly12-to-ser (G12S) amino acid substitution. Kerr et al. (2006) analyzed the HRAS gene in 43 patients with a clinical diagnosis of Costello syndrome and identified mutations in 37 (86%); G12S was the most common mutation, found in 30 of the 37 mutation-positive patients. Zampino et al. (2007) identified the G12S mutation in 8 of 9 unrelated patients with Costello syndrome. By analyzing the flanking genomic region, the authors determined that all patients had de novo mutations inherited from the father. There was an advanced age at conception in affected fathers transmitting the mutation. The phenotype was homogeneous. In a male infant with severe Costello syndrome, Lo et al. (2008) identified the G12S mutation in the HRAS gene. The patient had persistent neonatal hypoglycemia, hypocalcemia, right ventricular hypertrophy, and enlarged kidneys. He required pyloromyotomy for pyloric stenosis and inguinal hernia repair at age 3 months. He had complex upper and lower airway obstruction with a floppy tongue, narrow subglottic opening, and tracheobronchomalacia, requiring a tracheostomy with intermittent ventilatory support. Deterioration of his respiratory function led to the discovery of a pulmonary rhabdomyosarcoma, and he died at 2.25 years of age. Congenital Myopathy with Excess of Muscle Spindles Van der Burgt et al. (2007) identified a heterozygous G12S mutation in the HRAS gene in a patient with congenital myopathy with excess of muscle spindles (see 218040), a phenotypic variant of Costello syndrome. The patient, originally reported by Selcen et al. (2001), died at age 14 months of cardiorespiratory failure. He had generalized muscle weakness, areflexia, joint contractures, and clubfeet. Epidermal Nevus and Urothelial Cancer, Somatic Hafner et al. (2011) reported a 49-year-old man who had widespread mosaicism for a G12S mutation present in tissues derived from endoderm, ectoderm, and mesoderm, suggesting an embryonic mutation. The patient presented at 49 years of age with widespread congenital epidermal nevus (162900). At 19 years of age a urothelial cell carcinoma was detected in the bladder, and 2 new tumors were identified at 48 years of age. At age 49 a single metastatic lesion was identified in lung. Nevus Sebaceous, Somatic Groesser et al. (2012) identified a somatic G12S mutation in 3 (5%) of 65 nevus sebaceous tumors (see 162900). Woolly Hair Nevus, Somatic By paired whole-exome sequencing of DNA in affected tissue and blood from 2 unrelated girls with woolly hair nevus (see 162900), Levinsohn et al. (2014) identified heterozygosity for a somatic G12S mutation in the HRAS gene in both individuals. Analysis of hair bulbs from straight and curly patient hair confirmed that the G12S mutation was present in curly hair only. There was no evidence for loss of heterozygosity or a secondary somatic mutation, suggesting that HRAS mutation alone is sufficient to cause woolly hair nevus. (less)

Costello Syndrome In 3 Japanese and in 4 Italian patients with Costello syndrome (218040), Aoki et al. (2005) identified a germline 34G-A transition in the HRAS gene that caused a gly12-to-ser (G12S) amino acid substitution. Kerr et al. (2006) analyzed the HRAS gene in 43 patients with a clinical diagnosis of Costello syndrome and identified mutations in 37 (86%); G12S was the most common mutation, found in 30 of the 37 mutation-positive patients. Zampino et al. (2007) identified the G12S mutation in 8 of 9 unrelated patients with Costello syndrome. By analyzing the flanking genomic region, the authors determined that all patients had de novo mutations inherited from the father. There was an advanced age at conception in affected fathers transmitting the mutation. The phenotype was homogeneous. In a male infant with severe Costello syndrome, Lo et al. (2008) identified the G12S mutation in the HRAS gene. The patient had persistent neonatal hypoglycemia, hypocalcemia, right ventricular hypertrophy, and enlarged kidneys. He required pyloromyotomy for pyloric stenosis and inguinal hernia repair at age 3 months. He had complex upper and lower airway obstruction with a floppy tongue, narrow subglottic opening, and tracheobronchomalacia, requiring a tracheostomy with intermittent ventilatory support. Deterioration of his respiratory function led to the discovery of a pulmonary rhabdomyosarcoma, and he died at 2.25 years of age. Congenital Myopathy with Excess of Muscle Spindles Van der Burgt et al. (2007) identified a heterozygous G12S mutation in the HRAS gene in a patient with congenital myopathy with excess of muscle spindles (see 218040), a phenotypic variant of Costello syndrome. The patient, originally reported by Selcen et al. (2001), died at age 14 months of cardiorespiratory failure. He had generalized muscle weakness, areflexia, joint contractures, and clubfeet. Epidermal Nevus and Urothelial Cancer, Somatic Hafner et al. (2011) reported a 49-year-old man who had widespread mosaicism for a G12S mutation present in tissues derived from endoderm, ectoderm, and mesoderm, suggesting an embryonic mutation. The patient presented at 49 years of age with widespread congenital epidermal nevus (162900). At 19 years of age a urothelial cell carcinoma was detected in the bladder, and 2 new tumors were identified at 48 years of age. At age 49 a single metastatic lesion was identified in lung. Nevus Sebaceous, Somatic Groesser et al. (2012) identified a somatic G12S mutation in 3 (5%) of 65 nevus sebaceous tumors (see 162900). Woolly Hair Nevus, Somatic By paired whole-exome sequencing of DNA in affected tissue and blood from 2 unrelated girls with woolly hair nevus (see 162900), Levinsohn et al. (2014) identified heterozygosity for a somatic G12S mutation in the HRAS gene in both individuals. Analysis of hair bulbs from straight and curly patient hair confirmed that the G12S mutation was present in curly hair only. There was no evidence for loss of heterozygosity or a secondary somatic mutation, suggesting that HRAS mutation alone is sufficient to cause woolly hair nevus. (less)

Costello Syndrome In 3 Japanese and in 4 Italian patients with Costello syndrome (218040), Aoki et al. (2005) identified a germline 34G-A transition in the HRAS gene that caused a gly12-to-ser (G12S) amino acid substitution. Kerr et al. (2006) analyzed the HRAS gene in 43 patients with a clinical diagnosis of Costello syndrome and identified mutations in 37 (86%); G12S was the most common mutation, found in 30 of the 37 mutation-positive patients. Zampino et al. (2007) identified the G12S mutation in 8 of 9 unrelated patients with Costello syndrome. By analyzing the flanking genomic region, the authors determined that all patients had de novo mutations inherited from the father. There was an advanced age at conception in affected fathers transmitting the mutation. The phenotype was homogeneous. In a male infant with severe Costello syndrome, Lo et al. (2008) identified the G12S mutation in the HRAS gene. The patient had persistent neonatal hypoglycemia, hypocalcemia, right ventricular hypertrophy, and enlarged kidneys. He required pyloromyotomy for pyloric stenosis and inguinal hernia repair at age 3 months. He had complex upper and lower airway obstruction with a floppy tongue, narrow subglottic opening, and tracheobronchomalacia, requiring a tracheostomy with intermittent ventilatory support. Deterioration of his respiratory function led to the discovery of a pulmonary rhabdomyosarcoma, and he died at 2.25 years of age. Congenital Myopathy with Excess of Muscle Spindles Van der Burgt et al. (2007) identified a heterozygous G12S mutation in the HRAS gene in a patient with congenital myopathy with excess of muscle spindles (see 218040), a phenotypic variant of Costello syndrome. The patient, originally reported by Selcen et al. (2001), died at age 14 months of cardiorespiratory failure. He had generalized muscle weakness, areflexia, joint contractures, and clubfeet. Epidermal Nevus and Urothelial Cancer, Somatic Hafner et al. (2011) reported a 49-year-old man who had widespread mosaicism for a G12S mutation present in tissues derived from endoderm, ectoderm, and mesoderm, suggesting an embryonic mutation. The patient presented at 49 years of age with widespread congenital epidermal nevus (162900). At 19 years of age a urothelial cell carcinoma was detected in the bladder, and 2 new tumors were identified at 48 years of age. At age 49 a single metastatic lesion was identified in lung. Nevus Sebaceous, Somatic Groesser et al. (2012) identified a somatic G12S mutation in 3 (5%) of 65 nevus sebaceous tumors (see 162900). Woolly Hair Nevus, Somatic By paired whole-exome sequencing of DNA in affected tissue and blood from 2 unrelated girls with woolly hair nevus (see 162900), Levinsohn et al. (2014) identified heterozygosity for a somatic G12S mutation in the HRAS gene in both individuals. Analysis of hair bulbs from straight and curly patient hair confirmed that the G12S mutation was present in curly hair only. There was no evidence for loss of heterozygosity or a secondary somatic mutation, suggesting that HRAS mutation alone is sufficient to cause woolly hair nevus. (less)

Costello Syndrome In 3 Japanese and in 4 Italian patients with Costello syndrome (218040), Aoki et al. (2005) identified a germline 34G-A transition in the HRAS gene that caused a gly12-to-ser (G12S) amino acid substitution. Kerr et al. (2006) analyzed the HRAS gene in 43 patients with a clinical diagnosis of Costello syndrome and identified mutations in 37 (86%); G12S was the most common mutation, found in 30 of the 37 mutation-positive patients. Zampino et al. (2007) identified the G12S mutation in 8 of 9 unrelated patients with Costello syndrome. By analyzing the flanking genomic region, the authors determined that all patients had de novo mutations inherited from the father. There was an advanced age at conception in affected fathers transmitting the mutation. The phenotype was homogeneous. In a male infant with severe Costello syndrome, Lo et al. (2008) identified the G12S mutation in the HRAS gene. The patient had persistent neonatal hypoglycemia, hypocalcemia, right ventricular hypertrophy, and enlarged kidneys. He required pyloromyotomy for pyloric stenosis and inguinal hernia repair at age 3 months. He had complex upper and lower airway obstruction with a floppy tongue, narrow subglottic opening, and tracheobronchomalacia, requiring a tracheostomy with intermittent ventilatory support. Deterioration of his respiratory function led to the discovery of a pulmonary rhabdomyosarcoma, and he died at 2.25 years of age. Congenital Myopathy with Excess of Muscle Spindles Van der Burgt et al. (2007) identified a heterozygous G12S mutation in the HRAS gene in a patient with congenital myopathy with excess of muscle spindles (see 218040), a phenotypic variant of Costello syndrome. The patient, originally reported by Selcen et al. (2001), died at age 14 months of cardiorespiratory failure. He had generalized muscle weakness, areflexia, joint contractures, and clubfeet. Epidermal Nevus and Urothelial Cancer, Somatic Hafner et al. (2011) reported a 49-year-old man who had widespread mosaicism for a G12S mutation present in tissues derived from endoderm, ectoderm, and mesoderm, suggesting an embryonic mutation. The patient presented at 49 years of age with widespread congenital epidermal nevus (162900). At 19 years of age a urothelial cell carcinoma was detected in the bladder, and 2 new tumors were identified at 48 years of age. At age 49 a single metastatic lesion was identified in lung. Nevus Sebaceous, Somatic Groesser et al. (2012) identified a somatic G12S mutation in 3 (5%) of 65 nevus sebaceous tumors (see 162900). Woolly Hair Nevus, Somatic By paired whole-exome sequencing of DNA in affected tissue and blood from 2 unrelated girls with woolly hair nevus (see 162900), Levinsohn et al. (2014) identified heterozygosity for a somatic G12S mutation in the HRAS gene in both individuals. Analysis of hair bulbs from straight and curly patient hair confirmed that the G12S mutation was present in curly hair only. There was no evidence for loss of heterozygosity or a secondary somatic mutation, suggesting that HRAS mutation alone is sufficient to cause woolly hair nevus. (less)