ClinVar Genomic variation as it relates to human health

Peripheral neuropathy (present) , Optic disc pallor (present) , Lower limb spasticity (present) , Lower limb muscle weakness (present) , Generalized hypotonia (present) , Abnormality of vision (present) (less)

Rivolta et al. (2000) described a cys759-to-phe (C759F) missense mutation caused by a G-T change in the USH2A gene that was associated with autosomal recessive retinitis pigmentosa without hearing loss (RP39; 613809). The amino acid at this position is within the fifth laminin-epidermal growth factor-like domain and participates in a presumed disulfide bridge. The mutation was found in 4.5% of 224 patients with recessive RP. Rivolta et al. (2002) reported a patient with RP without hearing loss caused by a homozygous C759F mutation in the USH2A gene. Her father was heterozygous for this change, and her mother was a noncarrier. Further evaluation with microsatellite markers revealed that the patient had inherited 2 copies of chromosome 1 from her father and none from her mother. The 2 paternally derived copies of chromosome 1 were heteroallelic from the centromere to the proximal short and long arms. The distal regions of the short and long arms of chromosome 1 were homoallelic, including the region of 1q with the mutant USH2A allele. This genetic pattern is compatible with uniparental primary heterodisomy with regions of homozygosity arising through a nondisjunction event during paternal meiosis I and subsequent trisomy rescue or gamete complementation. A paternal second cousin of the patient also had RP and had an identical heterozygous mutation in the USH2A gene in the same codon. However, the analysis of an isocoding polymorphism 20 bp away and closely linked microsatellite markers in the patient and family members indicated that the 2 mutant alleles were unlikely to be identical by descent and that the 2 relatives fortuitously had RP and a mutation in the same codon of the USH2A gene. Pozo et al. (2015) noted that 15 families with RP had been reported to have a homozygous C759F variant (rs80338902) in the USH2A gene. In all reviewed cases, the segregation data either were not shown or were inconclusive. Pozo et al. (2015) restudied a Spanish family (S23) in which Bernal et al. (2003) had identified homozygosity for C759F in 2 affected and 2 unaffected sibs. By next-generation sequencing, they identified homozygosity for an R560C mutation in the PDE6B gene (180072.0008) that segregated with the disorder in the family and was absent in 200 control individuals. Pozo et al. (2015) suggested that the C759F variant might not be pathogenic and proposed genetic reevaluation of other reported families with the C759F variant. In a discovery cohort of 186 unrelated probands with autosomal recessive retinal degeneration without childhood hearing loss, Lenassi et al. (2015) found the c.2276G-T transversion in USH2A gene, resulting in a C759F substitution, in 11 alleles (once in homozygosity). In the replication cohort of 84 unrelated probands with autosomal recessive retinal degeneration, the allele was found 5 times, once in homozygosity; and in a third panel of 187 patients with nonsyndromic adult-onset autosomal recessive retinitis pigmentosa, it was found 5 times, once in homozygosity. Lenassi et al. (2015) noted that the C759F mutation is often considered to be the most common disease-causing variant in patients with nonsyndromic retinitis pigmentosa. To assess the role of the C759F mutation in autosomal recessive retinitis pigmentosa and Usher syndrome type 2, Perez-Carro et al. (2018) performed a comprehensive genetic and clinical study of 57 families with affected members who carried the C759F mutation on at least 1 allele. Of the 57 probands, 11 were homozygous for the mutation, 42 were compound heterozygous with another mutation in the USH2A gene, and the remaining 4 also carried mutations in RP1 (603937), PROM1 (604365), or CNGB1 (600724). The 2 patients with PROM1 and CNGB1 mutations, and 1 patient with mutated RP1, were homozygous for those mutations in addition to the C759F mutation in USH2A; the second patient with mutation in RP1 was heterozygous for that mutation. The authors noted that although the C759F variant is enriched in the Spanish population, no homozygous individuals had been identified in control populations, even in Spanish population databases. Perez-Carro et al. (2018) stated that the C759F mutation alters a highly conserved residue in a domain that enhances USH2A stability in the basement membrane by prompting its interaction with collagen IV (see 120070). The mutation was also predicted to disrupt a disulfide bridge, leading to erroneous protein folding and instability. While Pozo et al. (2015) had questioned the pathogenicity of the C759F variant, at least in homozygosity, Perez-Carro et al. (2018) pointed out that no other candidate variants in the USH2A or any other RP genes that could explain the phenotypes were found in their patients by next-generation sequencing. They concluded that C759F homozygosity is associated with a later diagnosis of RP and slower progression of visual field loss, with a very late hypoacusis diagnosis (around the seventh decade). (less)