ClinVar Genomic variation as it relates to human health

In 5 probands with severe Leber congenital amaurosis (LCA9; 608553), Koenekoop et al. (2012) identified a 769G-A transition in exon 5 of the NMNAT1 gene, resulting in a glu257-to-lys (E257K) substitution at a conserved residue in a protein-interaction domain interface, predicted to interfere with hexamer formation. The mutation was found in homozygosity in 1 proband, and was present in compound heterozygosity with another missense mutation in the NMNAT1 gene in the other 4 probands (see, e.g., 608700.0003-608700.0005). All mutations segregated with disease in each family and were not found in 200 controls. In red blood cells (RBCs) from the patient homozygous for E257K there was a significantly lower concentration of NAD compared with that in RBCs from his heterozygous mother, suggesting reduced enzymatic function of the mutant protein. Immunohistochemical studies in transfected HeLa cells demonstrated that whereas wildtype NMNAT1 showed strong nuclear staining, the E257K mutant stained strongly outside of the cell nucleus in the cytoplasm; in addition, the mutant protein was positive for ubiquitin staining, indicating that the mutation likely affects protein folding. In vitro assay showed significantly reduced enzymatic activity with the E257K mutant protein compared to wildtype. In 11 probands with severe LCA, Chiang et al. (2012) identified compound heterozygosity for the E257K mutation and another missense or nonsense mutation in the NMNAT1 gene (see, e.g., N273D, 608700.0003; V151F, 608700.0004; and W169X, 608700.0006). Chiang et al. (2012) stated that the allele frequency of E257K (rs150726175) was estimated to be 0.001, whereas the remainder of the variants had not been reported in any public database. In 6 probands with LCA, Falk et al. (2012) identified compound heterozygosity for the E257K mutation and another missense or frameshift mutation in the NMNAT1 gene. Perrault et al. (2012) identified the E257K variant on 1 allele in 23 of 29 probands with LCA in whom mutation in NMNAT1 was detected. In a 6-year-old Spanish boy with LCA, Bedoni et al. (2020) identified compound heterozygosity for the E257K variant and a 7.4-kb duplication within the NMNAT1 gene (608700.0010). In a 14-year-old Caucasian girl (case 2) with early-onset retinal dystrophy and coloboma-like macular atrophy, Nash et al. (2018) identified compound heterozygous mutations in the NMNAT1 gene: E257K and a c.53A-G transition, resulting in an asn18-to-ser (N18S; 608700.0014) substitution. The N18S variant was present in 5 of 276,912 alleles in the gnomAD database (minor allele frequency, 0.000018). The authors noted that ERG findings in this patient showed reduced photopic and scotopic responses, consistent with cone-rod dystrophy. In an Egyptian brother and sister with early-onset progressive retinal dysfunction and foveal hypoplasia, consistent with cone-rod dystrophy, Bedoukian et al. (2020) identified compound heterozygous mutations in the NMNAT1 gene: E257K and a c.245T-C transition, resulting in a val82-to-ala (V82A; 608700.0015) substitution. Their unaffected parents were each heterozygous for one of the mutations. In a sister and brother with childhood-onset rod-cone dystrophy with severe macular involvement, Kumaran et al. (2021) identified compound heterozygosity for the E257K and N18S mutations in the NMNAT1 gene. Their unaffected parents were each heterozygous for one of the mutations. (less)