ClinVar Miner

Submissions for variant NM_016038.4(SBDS):c.258+1G>C (rs113993992)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000020728 SCV000469856 pathogenic Shwachman-Diamond syndrome 1 2016-06-14 criteria provided, single submitter clinical testing 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.
GeneDx RCV000413600 SCV000490786 pathogenic not provided 2018-11-16 criteria provided, single submitter clinical testing The c.258+1 G>C variant has been reported previously in association with SDS (Boocock et al., 2003; Woloszynek et al., 2004). This splice site variant destroys the canonical splice donor site in intron 2. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Therefore, we interpret this variant as pathogenic.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768305 SCV000898942 pathogenic Shwachman-Diamond syndrome 1; Aplastic anemia 2018-05-02 criteria provided, single submitter clinical testing SBDS NM_016038.3 exon 2 c.258+1G>C: This variant has been reported in the literature in at least 2 individuals (zygosity unclear) with Shwachman-Diamond Syndrome (Boocock 2003 PMID:12496757, Woloszynek 2004 PMID:15284109). This variant is present in 3/126700 European alleles in the Genome Aggregation Database ( This variant is present in ClinVar (Variation ID:21538). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant alters the consensus splice sequence (+/- 1,2) which is predicted to result in an absent or abnormal protein. Loss of function has been reported as a disease mechanism for this gene and disease (Woloszynek 2004 PMID:15284109). In summary, this variant is classified as pathogenic .
GeneReviews RCV000020728 SCV000041302 pathologic Shwachman-Diamond syndrome 1 2008-07-17 no assertion criteria provided curation Converted during submission to Pathogenic.

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