Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Illumina Laboratory Services, |
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. |
Gene |
RCV000413600 | SCV000490786 | pathogenic | not provided | 2022-07-07 | criteria provided, single submitter | clinical testing | Canonical splice site variant in intron 2 of the SBDS gene, for which loss-of-function is a known mechanism of disease (Nelson & Meyers, 2018); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28971907, 23351992, 20301722, 12496757, 17916435, 24898207, 15284109) |
Center for Genomics, |
RCV000768305 | SCV000898942 | pathogenic | Shwachman-Diamond syndrome 1; Aplastic anemia | 2021-11-22 | 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 (http://gnomad.broadinstitute.org/rs113993992). 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 . |
Ambry Genetics | RCV002453265 | SCV002739607 | pathogenic | Inborn genetic diseases | 2016-11-03 | criteria provided, single submitter | clinical testing | The c.258+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 2 of the SBDS gene. This mutation was first reported in two alleles from 158 unrelated families with at least one individual with Shwachman-Diamond syndrome (SDS) (Boocock GR et al. Nat. Genet., 2003 Jan;33:97-101). In another study, this mutation was identified in conjunction with the common c.258+2T>C pathogenic mutation in an individual suspected to have SDS; however, the phase of the alterations was not provided (Woloszynek JR et al. Blood, 2004 Dec;104:3588-90). In our internal cohort, this mutation was confirmed in trans with a complex allele including c.258+2T>C in an individual with pancytopenia, pancreatic insufficiency, and skeletal abnormalities. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. |
Baylor Genetics | RCV003473116 | SCV004202335 | pathogenic | Aplastic anemia | 2023-09-14 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000020728 | SCV000041302 | not provided | Shwachman-Diamond syndrome 1 | no assertion provided | literature only |