ClinVar

Description

The p.N463D pathogenic mutation (also known as c.1387A>G), located in coding exon 1 of the FKRP gene, results from an A to G substitution at nucleotide position 1387. The asparagine at codon 463 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration has been reported in the homozygous state in multiple individuals with congenital muscular dystrophy, including hypotonia, motor delay, and elevated CK (MacLeod H et al. Neuromuscul. Disord., 2007 Apr;17:285-9; Navarro-Cobos MJ et al. Neuropediatrics, 2017 12;48:442-450; Lee AJ et al. Neurol Genet, 2019 Apr;5:e315). In addition, this variant has been reported in trans with a second FKRP alteration (Navarro-Cobos MJ et al. Neuropediatrics, 2017 12;48:442-450; Lee AJ et al. Neurol Genet, 2019 Apr;5:e315). It has been suggested that this might be a founder allele in individuals with Latino ancestry (Navarro-Cobos MJ et al. Neuropediatrics, 2017 12;48:442-450). Muscle biopsy from individuals homozygous for this alteration showed myopathic changes including variation in myofiber size, fatty replacement and endomysial fibrosis, absent alpha-dystroglycan staining, reduction in beta-dystroglycan as well as alpha-, beta-, and gamma-sarcoglycan staining, and mild focal reduction of dystrophin and merosin staining (MacLeod H et al. Neuromuscul. Disord., 2007 Apr;17:285-9). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.