ClinVar

Description

This variant affects the canonical splice donor site of intron 2 and is therefore predicted to interfere with splicing and result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This is a common Pathogenic variant found in individuals with Shwachman-Diamond syndrome, which arises from a gene conversion event with a nearby SBDS pseudogene (*see note below) (PMID: 20301722, 12496757, 19222471). It has been previously reported as a compound heterozygous, homozygous, and, less frequently, as a heterozygous change in patients with Shwachman-Diamond syndrome (PMID: 12496757, 14749921, 15860664, 22935661). Functional studies suggest that the c.258+2 T>C variant affects the protein's cellular localization and motility (PMID: 21695142). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.388% (1096/282568) and seen in the homozygous state in 2 individuals. Based on the available evidence, the c.258+2T>C variant is classified as Pathogenic. <b>*Note:</b> The SBDS gene has a highly homologous nonfunctional pseudogene called SBDSP. The majority of pathogenic variation in SBDS has been found to result from gene conversion (a process by which a small segment of the functional SBDS gene is replaced by a segment copied from the nonfunctional SBDSP pseudogene). The variants, c.258+2T>C and c.183_184delTAinsCT (p.Lys62Ter), are recurrent Pathogenic variants resulting from gene conversion. These variants have been reported in the compound heterozygous state (trans configuration) in multiple affected individuals. These variants have also been reported as a single complex allele, c.184A>T; 258+2T>C (cis configuration), which is then seen in the compound state with another Pathogenic variant on the second allele in affected individuals (PMID: 12496757, 29892551, 27290639, 28102861, 30109123).