ClinVar Miner

Submissions for variant NM_016038.4(SBDS):c.258+2T>C (rs113993993)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 20
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255013 SCV000321934 pathogenic not provided 2018-12-21 criteria provided, single submitter clinical testing The c.258+2 T>C pathogenic variant is a common pathogenic variant in SDS because it is present in a nearby SBDS pseudogene, an inactive gene with numerous pathogenic variants. Sections of the pseudogene can be transferred to the actual SBDS gene. The c.258+2 T>C variant has been published previously in association with Shwachman-Diamond syndrome (Boocock et al., 2003; Nakashima et al., 2004; Andolina et al., 2013). The variant destroys the canonical splice donor site in intron 2, and is expected to cause abnormal gene splicing resulting in a frameshift which is also predicted to cause protein truncation. Functional studies suggest that truncating variants, including c.258+2 T>C, may affect the protein's cellular localization and motility (Austin et al., 2005; Orelio et al., 2011). We interpret c.258+2 T>C as a pathogenic variant.
Genetic Services Laboratory,University of Chicago RCV000003347 SCV000596926 pathogenic Shwachman-Diamond syndrome 1 2016-10-27 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000506317 SCV000605055 pathogenic not specified 2017-01-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV000623539 SCV000740932 pathogenic Inborn genetic diseases 2014-06-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000003347 SCV000743792 pathogenic Shwachman-Diamond syndrome 1 2017-07-28 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000003347 SCV000745201 pathogenic Shwachman-Diamond syndrome 1 2016-05-18 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626935 SCV000747638 pathogenic Short stature; Deeply set eye; Agenesis of permanent teeth; Microcephaly; Splenomegaly 2017-01-01 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000255013 SCV000854947 pathogenic not provided 2018-02-26 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763594 SCV000894438 pathogenic Shwachman-Diamond syndrome 1; Aplastic anemia 2018-10-31 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000763594 SCV000898941 pathogenic Shwachman-Diamond syndrome 1; Aplastic anemia 2018-05-02 criteria provided, single submitter clinical testing SBDS NM_016038.3 exon 2 c.258+2T>C: This variant has been reported in the literature in several individuals with Shwachman-Diamond syndrome as homozygous or compound heterozygous (most often found in trans with c.183_184delinsCT) and is one of the most common pathogenic variants for this gene (Boocock 2003 PMID:12496757, Nakashima 2004 PMID:14749921, Austin 2005 PMID:15860664, Andolina 2013 PMID:22935661, Myers 2014 PMID:20301722). This variant is present in 0.3% (468/126574) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs113993993). This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:3196). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In addition, functional studies have shown a deleterious effect of this variant (Orelio 2011 PMID:21695142). 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.
Blueprint Genetics RCV000255013 SCV000928088 pathogenic not provided 2018-11-30 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000003347 SCV000967787 pathogenic Shwachman-Diamond syndrome 1 2018-12-03 criteria provided, single submitter clinical testing The c.258+2T>C variant in SBDS is one of the most common pathogenic variants ide ntified in individuals with Shwachman-Diamond syndrome (Boocock 2003, https://ww w.ncbi.nlm.nih.gov/books/NBK1756/). It has also been identified in 0.9% (236/250 74) of Finnish chromosomes and 2 homozygotes by gnomAD (http://gnomad.broadinsti tute.org); however, this allele frequency may not be accurate due to the presenc e of a pseudogene (SBDSP). This variant usually occurs as the result of a gene c onversion event as the c.258+2C>T variant is present in the inactive pseudogene. It is predicted to result in a frameshift described as p.Cys84TyrfsX4 (Boocock 2003, Orelio 2011). This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the SBDS gene is an established disease mech anism in autosomal recessive Shwachman-Diamond syndrome. In summary, this varian t meets criteria to be classified as pathogenic. ACMG/AMP Criteria applied: PVS1 , PM3_Very Strong, PS3.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000003347 SCV000996168 pathogenic Shwachman-Diamond syndrome 1 2018-07-10 criteria provided, single submitter clinical testing The c.258+2T>C variant is a canonical splice donor variant in the SBDS gene. The variant is one of the most common pathogenic variants in SBDS (PMID: 20301722), and has been reported by multiple laboratories in the ClinVar as pathogenic (variant ID: 3196). Functional studies suggest that the c.258+2 T>C variant affects the protein's cellular localization and motility (PMID: 21695142). The c.258+2T>C variant is present in ExAC at 0.39% (474/120486), but it is not present in the homozygous state. Based on the combined evidence, the variant is classified as pathogenic.
Institute of Human Genetics,Klinikum rechts der Isar RCV000003347 SCV001149915 pathogenic Shwachman-Diamond syndrome 1 2019-11-06 criteria provided, single submitter clinical testing
OMIM RCV000003347 SCV000023505 pathogenic Shwachman-Diamond syndrome 1 2007-08-15 no assertion criteria provided literature only
OMIM RCV000003348 SCV000023506 risk factor Aplastic anemia, susceptibility to 2007-08-15 no assertion criteria provided literature only
GeneReviews RCV000003347 SCV000041303 pathologic Shwachman-Diamond syndrome 1 2008-07-17 no assertion criteria provided curation Converted during submission to Pathogenic.
Donald Williams Parsons Laboratory,Baylor College of Medicine RCV000003347 SCV000599973 pathogenic Shwachman-Diamond syndrome 1 2015-09-30 no assertion criteria provided research This variant has been previously reported as disease-causing. It would be pathogenic in a recessive state; heterozygotes would be carriers for the condition. It was found once in our study heterozygous in a 12-year-old male with pilocytic astrocytoma.
Reproductive Health Research and Development,BGI Genomics RCV000003347 SCV001142368 pathogenic Shwachman-Diamond syndrome 1 2020-01-06 no assertion criteria provided curation NG_007277.1(NM_016038.2):c.258+2T>C in the SBDS gene has an allele frequency of 0.009 in European (Finnish) subpopulation in the gnomAD database. Andolina JR et al. identified compound heterozygous mutations c183_184 TA>CT and c.258+2 T>C in two patients with Shwachman-Diamond syndrome (PMID: 22935661). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM3; PP4.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000003347 SCV001162248 likely pathogenic Shwachman-Diamond syndrome 1 no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.