current
NMNAT1:c.451G>T (p.Val151Phe) AND Leber congenital amaurosis 9
current
classified by single submitter
Pathogenic
germline
human
not provided
curation
In a European female with severe Leber congenital amaurosis (LCA9; 608553), Koenekoop et al. (2012) identified compound heterozygosity for a 451G-A transition in exon 5 of the NMNAT1 gene, resulting in a val151-to-phe (V151F) substitution at a conserved residue in the adenylyltransferase domain, and an E257K substitution (608700.0002). The mutations segregated with disease in the family and were not found in 200 controls. In vitro assays demonstrated that both mutant proteins had significantly reduced enzymatic activity compared to wildtype.
22842230
In a 26-year-old Canadian man of Greek ancestry with severe LCA, Chiang et al. (2012) identified compound heterozygosity for the V151F and E257K mutations in the NMNAT1 gene. At 6 months of age, the patient was diagnosed with retinitis pigmentosa (see 268000), but the diagnosis was later changed to LCA. Major vision loss occurred around 18 years of age, with colors and shapes still seen at age 20, at which time he began using a guide dog. Colors and shapes were lost at 22 years and 24 years of age, respectively, and by 26 years of age, the patient could only distinguish between light and dark. Eye examination showed wandering eye movements, macular atrophic lesions, attenuated vessels, and bone spicule pigmentation.
22842231
NMNAT1:c.451G>T (p.Val151Phe)
NM_022787.3:c.451G>T
NG_032954.1:g.43885G>T
NC_000001.10:g.10042370G>T
NP_073624.2:p.Val151Phe
missense
V151F
VAL151PHE
1p36.2
nicotinamide nucleotide adenylyltransferase 1
NMNAT1
Leber congenital amaurosis 9
Leber Congenital Amaurosis
LCA9
Leber congenital amaurosis (LCA), a severe dystrophy of the retina, typically becomes evident in the first year of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia, and keratoconus. Visual acuity is rarely better than 20/400. A characteristic finding is Franceschetti's oculo-digital sign, comprising eye poking, pressing, and rubbing. The appearance of the fundus is extremely variable. While the retina may initially appear normal, a pigmentary retinopathy reminiscent of retinitis pigmentosa is frequently observed later in childhood. The electroretinogram (ERG) is characteristically "nondetectable" or severely subnormal.
Neonatal/infancy
1-9 / 100 000
20301475
current
Pathogenic
germline
human
not provided
curation
In a European female with severe Leber congenital amaurosis (LCA9; 608553), Koenekoop et al. (2012) identified compound heterozygosity for a 451G-A transition in exon 5 of the NMNAT1 gene, resulting in a val151-to-phe (V151F) substitution at a conserved residue in the adenylyltransferase domain, and an E257K substitution (608700.0002). The mutations segregated with disease in the family and were not found in 200 controls. In vitro assays demonstrated that both mutant proteins had significantly reduced enzymatic activity compared to wildtype.
22842230
In a 26-year-old Canadian man of Greek ancestry with severe LCA, Chiang et al. (2012) identified compound heterozygosity for the V151F and E257K mutations in the NMNAT1 gene. At 6 months of age, the patient was diagnosed with retinitis pigmentosa (see 268000), but the diagnosis was later changed to LCA. Major vision loss occurred around 18 years of age, with colors and shapes still seen at age 20, at which time he began using a guide dog. Colors and shapes were lost at 22 years and 24 years of age, respectively, and by 26 years of age, the patient could only distinguish between light and dark. Eye examination showed wandering eye movements, macular atrophic lesions, attenuated vessels, and bone spicule pigmentation.
22842231
NMNAT1, VAL151PHE
VAL151PHE
NMNAT1
LEBER CONGENITAL AMAUROSIS 9