ClinVar

Description

The c.700C>T (p.R234*) alteration, located in exon 9 (coding exon 7) of the WDR45 gene, consists of a C to T substitution at nucleotide position 700. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 234. Premature stop codons are typically deleterious in nature (Richards, 2015). The alteration is not observed in healthy cohorts:_x000D_ Based on data from the NHLBI Exome Sequencing Project (ESP), the WDR45 c.700C>T (p.R234*) alteration was not observed among 6,453 individuals tested (0.0%). Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP). Though some variants may appear to be rare due to database-specific ethnic underrepresentation, rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012). IF USED, PULL THESE INTO REFERENCES:_x000D_ Kryukov GV, et al. (2007) Am J Hum Genet 80:727-739. Tennessen JA, et al. (2012) Science 337(64):64-69. The amino acid change has been observed in affected individuals: _x000D_ The c.700C>T (p.R234*) alteration has been reported in a 39 year-old female patient with beta-propeller protein-associated neurodegeneration (BPAN), an X-linked dominant form of neurodegeneration with brain iron accumulation (Haack, 2012; Hayflick, 2013). This patient's phenotype included developmental delay and intellectual disability, progressive psychomotor slowing in adolescence, dystonia and Parkinsonism with a positive response to L-DOPA, limited expressive language, stroke, and epilepsy characterized by absence, atonic, and febrile seizures. Brain MRI in this patient revealed iron accumulation in the substantia nigra and globus pallidus and T1 hyperintense "halo" in the midbrain. Based on the available evidence, this alteration is classified as pathogenic.