current
NMNAT1:c.817A>G (p.Asn273Asp) AND Leber congenital amaurosis 9
current
classified by single submitter
Pathogenic
germline
human
not provided
curation
In a 56-year-old French Canadian woman with severe Leber congenital amaurosis (LCA9; 608553), Koenekoop et al. (2012) identified compound heterozygosity for an 817A-G transition in exon 5 of the NMNAT1 gene, resulting in an asn273-to-asp (N273D) substitution at a conserved residue, 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 an 8-year-old Canadian boy of western European ancestry who had severe LCA, Chiang et al. (2012) identified compound heterozygosity for the N273D and E257K mutations in the NMNAT1 gene. The E257K and N273D mutations were inherited from his unaffected mother and father, respectively, and a third mutation was detected on the paternal allele as well: a 457C-G transversion in the NMNAT1 gene, resulting in a leu153-to-val (L153V; 608700.0008) substitution near the site of ligand binding, predicted to disturb local interactions and affect enzymatic activity. At 7 years of age, ERG showed primarily cone dysfunction rather than profound loss of all responses, and the patient's diagnosis was revised from 'variant LCA' to 'cone-rod dystrophy.'
22842231
NMNAT1:c.817A>G (p.Asn273Asp)
NM_022787.3:c.817A>G
NG_032954.1:g.44251A>G
NC_000001.10:g.10042736A>G
NP_073624.2:p.Asn273Asp
missense
N273D
ASN273ASP
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 56-year-old French Canadian woman with severe Leber congenital amaurosis (LCA9; 608553), Koenekoop et al. (2012) identified compound heterozygosity for an 817A-G transition in exon 5 of the NMNAT1 gene, resulting in an asn273-to-asp (N273D) substitution at a conserved residue, 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 an 8-year-old Canadian boy of western European ancestry who had severe LCA, Chiang et al. (2012) identified compound heterozygosity for the N273D and E257K mutations in the NMNAT1 gene. The E257K and N273D mutations were inherited from his unaffected mother and father, respectively, and a third mutation was detected on the paternal allele as well: a 457C-G transversion in the NMNAT1 gene, resulting in a leu153-to-val (L153V; 608700.0008) substitution near the site of ligand binding, predicted to disturb local interactions and affect enzymatic activity. At 7 years of age, ERG showed primarily cone dysfunction rather than profound loss of all responses, and the patient's diagnosis was revised from 'variant LCA' to 'cone-rod dystrophy.'
22842231
NMNAT1, ASN273ASP
ASN273ASP
NMNAT1
LEBER CONGENITAL AMAUROSIS 9