ClinVar Miner

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

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
Blueprint Genetics RCV000255013 SCV000928088 pathogenic not provided 2018-11-30 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000763594 SCV000898941 pathogenic Shwachman syndrome; 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.
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
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000003347 SCV000745201 pathogenic Shwachman syndrome 2016-05-18 criteria provided, single submitter clinical testing
Donald Williams Parsons Laboratory,Baylor College of Medicine RCV000003347 SCV000599973 pathogenic Shwachman syndrome 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.
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 syndrome; Aplastic anemia 2018-10-31 criteria provided, single submitter clinical testing
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.
GeneReviews RCV000003347 SCV000041303 pathologic Shwachman syndrome 2008-07-17 no assertion criteria provided curation Converted during submission to Pathogenic.
Genetic Services Laboratory, University of Chicago RCV000003347 SCV000596926 pathogenic Shwachman syndrome 2016-10-27 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000003347 SCV000743792 pathogenic Shwachman syndrome 2017-07-28 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000003347 SCV000967787 pathogenic Shwachman syndrome 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.
OMIM RCV000003347 SCV000023505 pathogenic Shwachman syndrome 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

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