ClinVar Genomic variation as it relates to human health

In a family segregating congenital cerulean cataract (CTRCT3; 601547) mapped to chromosome 22 by Kramer et al. (1996), Litt et al. (1997) found that affected individuals had a heterozygous chain-terminating mutation in CRYBB2. Of the 3 crystallin genes in the critical region, only CRYBB2 is strongly expressed in the adult lens. Hence, they chose this gene as the initial target for mutation screening. Detection of the mutation was assisted by the availability of an affected homozygote who was found to have a G-to-A transition in the antisense strand at the position of the first base of the codon normally encoding glutamine residue 155. This mutation created a stop codon that truncated the beta-B2-crystallin polypeptide by 51 residues (Q155X). The mutation also created a BfaI site, allowing convenient testing for its presence in family members. This family was originally reported by Bodker et al. (1990), who found that visual acuity was normal to mildly decreased until adult life except in 1 female, the product of affected first cousins, who was born with bilateral microphthalmia. They speculated that this represented the homozygous state. Gill et al. (2000) studied a 4-generation Swiss family with autosomal dominant Coppock-like cataract (604307) and mapped the phenotype to the 22q11.2-q13.1 region by linkage analysis. Direct cycle sequencing of exons 1 through 6 of the CRYBB2 gene identified a C-to-T transition at nucleotide 14 of exon 6, which results in an in-frame premature stop codon that truncates the beta-B2 crystallin polypeptide by 51 residues. Penetrance appeared to be complete. The study of Gill et al. (2000) demonstrated that the Coppock-like cataract phenotype is genetically heterogeneous; causative mutation had been found in the CRYGC gene (123680.0001). In affected members of a 5-generation Indian family that exhibited sutural cataract with punctate and cerulean opacities (601547), Vanita et al. (2001) identified the Q155X mutation and also found a second variant in the CRYBB2 gene, a silent 483C-T transition in exon 6 (123620.0002) that was in complete cosegregation with the phenotype. Alignment of the crystallin gene sequences showed that the Q155X and 483C-T alterations defined a fragment of at least 9 bp in the CRYBB2 mutant that were identical to the 'normal' sequence in the CRYBB2P1 pseudogene, and the fragment was flanked upstream by 28 bp and downstream by 67 bp where the gene and pseudogene are identical. Vanita et al. (2001) concluded that both variants had arisen by a gene conversion event between the CRYBB2 and its nearby pseudogene, CRYBB2P1. In affected members of a 4-generation Chilean family (ADC53) segregating autosomal dominant cataract with variable location, morphology, color, and density of the opacities (601547) among affected family members, Bateman et al. (2007) identified the Q155X mutation and the 483C-T silent polymorphism. Because the Indian family reported by Vanita et al. (2001) and this Chilean family had the same exon 6 CRYBB2 sequence but different haplotypes, Bateman et al. (2007) postulated that the alterations in each family were caused by independent gene conversion events. (less)