ClinVar

Description

The c.258+1G>C variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.258+1G>C variant has been reported in three studies and is found in a total of four patients with Shwachmann-Diamond syndrome in a compound heterozygous state (Boocock et al. 2003; Woloszynek et al. 2004; Hassan et al. 2009). The variant was absent from 148 controls and is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. The c.258+1G>C splice donor variant interrupts the intron 2 invariant splice donor site which results in the use of a cryptic splice donor site at cDNA position 251-252. The abnormally spliced mRNA results in a frameshift at amino acid position 84 with subsequent premature truncation of the protein after an additional three amino acids (Boocock et al. 2003; Woloszynek et al. 2004). A different variant at the c.258+2 position in the same intron 2 invariant splice donor site results in an identical frameshift and is one of the most common known pathogenic variants in the SBDS gene. Based on the collective evidence, the c.258+1G>C variant is classified as pathogenic for Shwachmann-Diamond syndrome.