NM_016038.4(SBDS):c.258+2T>C AND Shwachman-Diamond syndrome 1
- Germline classification:
- Pathogenic/Likely pathogenic (31 submissions)
- Last evaluated:
- Mar 17, 2024
- Review status:
- 2 stars out of maximum of 4 starscriteria provided, multiple submitters, no conflicts
- Somatic classification
of clinical impact: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Somatic classification
of oncogenicity: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Record status:
- current
- Accession:
- RCV000003347.48
Allele description [Variation Report for NM_016038.4(SBDS):c.258+2T>C]
NM_016038.4(SBDS):c.258+2T>C
- Gene:
- SBDS:SBDS ribosome maturation factor [Gene - OMIM - HGNC]
- Variant type:
- single nucleotide variant
- Cytogenetic location:
- 7q11.21
- Genomic location:
- Preferred name:
- NM_016038.4(SBDS):c.258+2T>C
- Other names:
- c.258+2T>C
- HGVS:
- NC_000007.14:g.66994210A>G
- NG_007277.1:g.6392T>C
- NG_033069.1:g.2406A>G
- NM_016038.4:c.258+2T>CMANE SELECT
- LRG_104t1:c.258+2T>C
- LRG_104:g.6392T>C
- NC_000007.13:g.66459197A>G
- NM_016038.2:c.258+2T>C
- NM_016038.2:c.[258+2T>C]
- NM_016038.3:c.258+2T>C
This HGVS expression did not pass validation- Nucleotide change:
- IVS2DS, T-C, +2
- Links:
- OMIM: 607444.0002; dbSNP: rs113993993
- NCBI 1000 Genomes Browser:
- rs113993993
- Molecular consequence:
- NM_016038.4:c.258+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
- Functional consequence:
- effect on RNA splicing [Variation Ontology: 0362]
- Observations:
- 1
Condition(s)
Assertion and evidence details
| Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
|---|---|---|---|---|---|---|
| SCV000023505 | OMIM | no assertion criteria provided | Pathogenic (Aug 15, 2007) | germline | literature only | |
| SCV000041303 | GeneReviews | no classification provided | not provided | germline | literature only | |
| SCV000599973 | Donald Williams Parsons Laboratory, Baylor College of Medicine - CSER-BASIC3
| no assertion criteria provided | Pathogenic (Sep 30, 2015) | germline | research | |
| SCV000743792 | Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus | criteria provided, single submitter (ACGS Guidelines, 2013) | Pathogenic (Jul 28, 2017) | germline | clinical testing | |
| SCV000745201 | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus | criteria provided, single submitter (ACGS Guidelines, 2013) | Pathogenic (May 18, 2016) | germline | clinical testing | |
| SCV000967787 | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | criteria provided, single submitter (LMM Criteria) | Pathogenic (Dec 3, 2018) | germline | clinical testing | |
| SCV000996168 | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Jul 10, 2018) | germline | clinical testing | |
| SCV001142368 | Reproductive Health Research and Development, BGI Genomics | no assertion criteria provided | Pathogenic (Jan 6, 2020) | germline | curation | |
| SCV001149915 | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | criteria provided, single submitter (Classification criteria August 2017) | Pathogenic (Dec 16, 2021) | paternal, inherited | clinical testing | |
| SCV001162248 | NIHR Bioresource Rare Diseases, University of Cambridge | no assertion criteria provided | Likely pathogenic | unknown | research | |
| SCV001440896 | Institute of Human Genetics, University of Leipzig Medical Center | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Dec 16, 2021) | unknown | clinical testing | |
| SCV001522750 | Baylor Genetics | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (May 27, 2020) | unknown | clinical testing | |
| SCV001976664 | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Oct 1, 2021) | paternal | clinical testing | |
| SCV002019993 | Revvity Omics, Revvity | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Nov 7, 2023) | germline | clinical testing | |
| SCV002028325 | Centogene AG - the Rare Disease Company | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Nov 5, 2021) | germline | clinical testing | |
| SCV002030085 | Baylor Genetics - CSER-TexasKidsCanSeq | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Feb 9, 2021) | maternal | clinical testing | |
| SCV002038505 | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Dec 16, 2021) | germline | clinical testing | |
| SCV002038567 | Illumina Laboratory Services, Illumina | criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) | Pathogenic (May 12, 2021) | unknown | clinical testing | |
| SCV002072017 | Genetic Services Laboratory, University of Chicago | no assertion criteria provided | Pathogenic (Jan 10, 2022) | germline | clinical testing | |
| SCV002073333 | Neuberg Centre For Genomic Medicine, NCGM | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic | germline | clinical testing | |
| SCV002097659 | New York Genome Center - CSER-NYCKidSeq | criteria provided, single submitter (NYGC Assertion Criteria 2020) | Pathogenic (Jul 9, 2020) | germline | clinical testing | |
| SCV002505974 | Bioinformatics Unit, Institut Pasteur de Montevideo | criteria provided, single submitter (ACMG Guidelines, 2015) | Likely pathogenic (May 3, 2022) | germline | clinical testing | |
| SCV002519003 | Mendelics | criteria provided, single submitter (Mendelics Assertion Criteria 2019) | Pathogenic (May 4, 2022) | germline | clinical testing | |
| SCV002557194 | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
| criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Sep 2, 2022) | germline | clinical testing | |
| SCV002569121 | Genetics Laboratory, Department of Biology, Semnan University | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Dec 30, 2020) | inherited | case-control | |
| SCV003807583 | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Apr 7, 2022) | germline | clinical testing | |
| SCV003853254 | Lifecell International Pvt. Ltd | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic | germline | clinical testing | |
| SCV003922130 | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (May 2, 2023) | germline | curation | |
| SCV004037087 | Suma Genomics | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic | germline | clinical testing | |
| SCV004805074 | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | criteria provided, single submitter (ACMG Guidelines, 2015) | Likely pathogenic (Mar 17, 2024) | germline | research | |
| SCV004813118 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) | Pathogenic (Feb 8, 2024) | germline | clinical testing |
Summary from all submissions
| Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
|---|---|---|---|---|---|---|---|---|
| not provided | germline | yes | 4 | not provided | not provided | 2 | not provided | clinical testing |
| not provided | germline | no | 1 | not provided | not provided | not provided | not provided | clinical testing |
| not provided | germline | not provided | 1 | 1 | not provided | not provided | not provided | literature only, clinical testing |
| not provided | germline | unknown | 1 | not provided | not provided | 1 | not provided | clinical testing, research, literature only, curation |
| not provided | inherited | yes | 1 | not provided | not provided | not provided | not provided | clinical testing |
| not provided | maternal | yes | not provided | not provided | not provided | not provided | not provided | clinical testing |
| not provided | paternal | yes | 2 | not provided | not provided | not provided | not provided | clinical testing |
| not provided | unknown | yes | 2 | not provided | not provided | 2 | not provided | clinical testing, research |
| not provided | unknown | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing |
| Asian | germline | yes | 1 | not provided | not provided | not provided | not provided | clinical testing |
| Hispanic Americans | germline | unknown | 1 | 1 | not provided | not provided | not provided | research |
| Semnan | inherited | yes | 1 | not provided | not provided | not provided | not provided | case-control |
Citations
PubMed
Hematologic abnormalities in Shwachman Diamond syndrome: lack of genotype-phenotype relationship.
Kuijpers TW, Alders M, Tool AT, Mellink C, Roos D, Hennekam RC.
Blood. 2005 Jul 1;106(1):356-61. Epub 2005 Mar 15.
- PMID:
- 15769891
Mutations in the SBDS gene in acquired aplastic anemia.
Calado RT, Graf SA, Wilkerson KL, Kajigaya S, Ancliff PJ, Dror Y, Chanock SJ, Lansdorp PM, Young NS.
Blood. 2007 Aug 15;110(4):1141-6. Epub 2007 May 3.
- PMID:
- 17478638
- PMCID:
- PMC1939897
Details of each submission
From OMIM, SCV000023505.4
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | literature only | PubMed (4) |
Description
Shwachman-Diamond Syndrome 1
For discussion of the splice site mutation in the SBDS gene (IVS2DS+2T-C) that was found in compound heterozygous state in patients with Shwachman-Diamond syndrome (SDS1; 260400) by Boocock et al. (2003) and Kuijpers et al. (2005), see 607444.0001. Boocock et al. (2003) referred to this mutation as 258+2T-C.
Nakashima et al. (2004) identified this mutation in affected members of 4 Japanese families with SDS, making it the most prevalent mutation. Recurrent gene conversion was considered the most likely explanation for the recurrence, rather than founder effect.
Aplastic Anemia, Susceptibility to
Calado et al. (2007) identified heterozygosity for the IVS2DS+2T-C mutation in 4 of 91 unrelated patients with aplastic anemia (609135). These patients were younger on average (5 to 19 years) compared to other patients with aplastic anemia. Two mothers tested were carriers of the mutation; these 2 and another mother who was not tested had histories of subclinical mild anemia. Heterozygous mutation carriers had partial loss of SBDS protein expression, indicating haploinsufficiency. Although telomere shortening was observed in patients' granulocytes, lymphocytes had normal telomere length. None of the patients with aplastic anemia had pancreatic exocrine failure or skeletal anomalies as seen in SDS. One of the 4 probands was also heterozygous for a presumed pathogenic variant in the TERT gene (187270).
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | not provided | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From GeneReviews, SCV000041303.2
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | literature only | not provided |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Donald Williams Parsons Laboratory, Baylor College of Medicine - CSER-BASIC3, SCV000599973.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | Hispanic Americans | 1 | not provided | not provided | research (GTR000508680.4) | PubMed (11) |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | (GTR000508680.4) | 1 | not provided | 1 | not provided |
From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV000743792.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV000745201.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000967787.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 1 | not provided | not provided | clinical testing | PubMed (5) |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | not provided | not provided | not provided | not provided | 1 | not provided | 1 | not provided | |
From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV000996168.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 1 | not provided | not provided | clinical testing | PubMed (1) |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | 1 | not provided | not provided | 1 | not provided | not provided | not provided | |
From Reproductive Health Research and Development, BGI Genomics, SCV001142368.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | curation | not provided |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV001149915.3
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 1 | not provided | not provided | clinical testing | not provided |
| 2 | not provided | 1 | not provided | not provided | clinical testing | not provided |
| 3 | not provided | 1 | not provided | not provided | clinical testing | not provided |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | paternal | yes | not provided | not provided | not provided | 1 | not provided | not provided | not provided | |
| 2 | paternal | yes | not provided | not provided | not provided | 1 | not provided | not provided | not provided | |
| 3 | inherited | yes | not provided | not provided | not provided | 1 | not provided | not provided | not provided | |
From NIHR Bioresource Rare Diseases, University of Cambridge, SCV001162248.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 1 | not provided | not provided | research | PubMed (1) |
| 2 | not provided | 1 | not provided | not provided | research | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | unknown | yes | 1 | not provided | not provided | 1 | not provided | not provided | not provided | |
| 2 | unknown | yes | 1 | not provided | not provided | 1 | not provided | not provided | not provided | |
From Institute of Human Genetics, University of Leipzig Medical Center, SCV001440896.2
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
This variant was identified as homozygous._x000D_ Criteria applied: PVS1, PS3, PS4
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | unknown | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Baylor Genetics, SCV001522750.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | unknown | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV001976664.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
PVS1, PP2, PP5
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | paternal | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Revvity Omics, Revvity, SCV002019993.3
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Centogene AG - the Rare Disease Company, SCV002028325.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Baylor Genetics - CSER-TexasKidsCanSeq, SCV002030085.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | maternal | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV002038505.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 1 | not provided | not provided | clinical testing | PubMed (2) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | no | not provided | not provided | not provided | 1 | not provided | not provided | not provided | |
From Illumina Laboratory Services, Illumina, SCV002038567.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (6) |
Description
The SBDS c.258+2T>C variant, also described as p.Cys84fsTer3, impacts the canonical splice donor site and results in an 8-bp deletion consistent with the use of a cryptic splice site and causing a frameshift and premature termination of the protein (Boocock et al. 2003). This variant, which occurs as a result of a gene conversion event with the nearby and highly homologous pseudogene SBDSP, is one of the most common disease-associated alleles in the SBDS gene (Nelson and Myers 2018). Across a small selection of the available literature, the c.258+2T>C variant was identified in 195 individuals with a confirmed or probable diagnosis of Shwachman-Diamond syndrome, including in a homozygous state in 13 individuals and in a compound heterozygous state in 182 individuals, 119 of whom carried the c.183_184delTAinsCT (p.Lys62Ter) variant, another common gene conversion variant, as the second variant (Boocock et al. 2003; Woloszynek et al. 2004; Myers et al. 2014; Cho et al. 2015; Ipatova et al. 2019). The c.258+2T>C variant was absent from 148 control individuals (Boocock et al. 2003; Woloszynek et al. 2004) but is reported at a frequency of 0.009412 in the European (Finnish) population of the Genome Aggregation Database (version 2.1.1). This population also includes two individuals who appear to be homozygous for this variant, though there are no homozygous individuals reported in a more recent version of the database (version 3.1.1). The presence of the SBDSP pseudogene may complicate the accurate reporting of the variant frequency in the population (Nelson and Myers 2018). In a functional study, Orelio et al. (2011) transiently transfected HeLa cells with GFP constructs containing full length or truncated protein due to the c.258+2T>C variant. The authors observed that the full-length protein was localized in both the nucleus and cytoplasm, while the truncated protein was mainly detected in the nucleus. The presence of the variant also affected nuclear import of SBDS proteins. Based on the available evidence, the c.258+2T>C variant is classified as pathogenic for Shwachman-Diamond syndrome.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | unknown | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Genetic Services Laboratory, University of Chicago, SCV002072017.3
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
Description
This pathogenic sequence change has previously been described in individuals with Shwachman- Diamond syndrome in the homozygous or compound heterozygous state with other pathogenic changes (PMIDs 12496757, 27127007, 21695142,15284109, 15942154). This sequence change was also identified in 4 individuals in the heterozygous state with apparently acquired aplastic anemia and short telomeres in granulocytes (PMID: 17478638); however further studies with larger populations are required to establish the association. Functional studies have shown that this sequence change results in a non-expressed product and impairs SBDS function (PMID 17478638). These collective evidences indicate that this sequence change is pathogenic.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Neuberg Centre For Genomic Medicine, NCGM, SCV002073333.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
The splice donor variant c.258+2T>C in SBDS (NM_016038.4) is one amongst the three commmon pathogenic mutations reported in 76% of the alleles with Schwamann Diamond syndrome (Nelson AS et al,2018). All the three common pathogenic variants including c.258+2T>C have arisen from gene conversion events with the pseudogene SBDSP. The c.258+2T>C variant is observed in 207/21,616 (0.9576%) alleles from individuals of Finnish background in gnomAD Exomes and in 4/1,008 (0.3968%) alleles from individuals of East Asian background in 1000 Genomes. However this cannot be considered as an estimate of the true allele frequency due to presence of pseudogene. The variant affects an invariant splice nucleotide and is predicted to cause loss of function. Functional studies have shown a deleterious effect (Orelio et al,2011). The variant has been submitted to ClinVar as Pathogenic. For these reasons, this variant has been classified as Pathogenic.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From New York Genome Center - CSER-NYCKidSeq, SCV002097659.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 1 | not provided | not provided | clinical testing | not provided |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | 1 | not provided | not provided | 1 | not provided | not provided | not provided | |
From Bioinformatics Unit, Institut Pasteur de Montevideo, SCV002505974.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | 1 | not provided | not provided | clinical testing | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | not provided | not provided | not provided | 1 | not provided | not provided | not provided | |
From Mendelics, SCV002519003.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002557194.2
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (3) |
Description
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Shwachman-Diamond syndrome (MIM#260400). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RT-PCR analysis of patient cells showed an 8bp deletion at the end of exon 2 consistent with the use of an upstream cryptic splice donor site. The deletion results in a frameshift and a premature termination codon (p.Cys84Tyrfs*4) (PMID: 12496757;15860664). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (1092 heterozygotes, 2 homozygotes). (SP) 0311 - Alternative nucleotide changes at the same canonical splice site are present in gnomAD (v2 & v3) (highest allele count: 3 heterozygotes, 0 homozygotes). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been previously reported as pathogenic in many patients with Shwachman-Diamond syndrome and is one of the most common pathogenic variants in cases of SBDS (ClinVar, PMIDs: 12496757 and 32150944, Nelson and Myers (2018)). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (Sanger analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | no | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Genetics Laboratory, Department of Biology, Semnan University, SCV002569121.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | Semnan | 1 | not provided | not provided | case-control | PubMed (1) |
Description
The identified mutation changes the splicing process of SBDS gene.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | inherited | yes | not provided | not provided | not provided | 1 | not provided | not provided | not provided | |
From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV003807583.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 1 | not provided | not provided | clinical testing | PubMed (1) |
Description
ACMG classification criteria: PVS1 strong, PS3 supporting, PM3 very strong
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | 1 | not provided | not provided | 1 | not provided | not provided | not provided | |
From Lifecell International Pvt. Ltd, SCV003853254.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | Asian | 1 | not provided | not provided | clinical testing | PubMed (2) |
Description
A Heterozygous Splice site donor variant c.258+2T>C in Exon 2 of the SBDS gene that results in the amino acid substitution was identified. The observed variant has a minor allele frequency of 0.00388/0.00386 in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/Likely Pathogenic [Variant ID: 3196]. This varaint is reported for Shwachman-Diamond syndrome and functional studies suggest that the c.258+2 T>C variant affects the protein's cellular localization and motility (Orelio C et . al., 2011). For these reasons, this variant has been classified as Pathogenic.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | not provided | not provided | not provided | 1 | not provided | not provided | not provided | |
From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV003922130.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | curation | PubMed (1) |
Description
The heterozygous c.258+2T>C variant in SBDS was identified by our study, in the compound heterozygous state along with a pathogenic variant (ClinVar Variation ID: 265256), in one individual with Swachman-Diamond syndrome. This individual also carried a pathogenic variant (ClinVar Variation ID: 265256), however the phase of these variants are unknown at this time. The c.258+2T>C variant in SBDS has been reported in over 108 unrelated individuals with Swachman-Diamond syndrome (PMID: 15769891, PMID: 15860664, PMID: 12496757) but has been identified in 0.8% (88/10582) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs113993993); however, this allele frequency may not be accurate due to the presence of a pseudogene (SBDSP). This variant has also been reported in ClinVar (Variation ID: 3196) and has been interpreted as pathogenic by multiple submitters. Of these 108 individuals, 9 were homozygotes (PMID: 15860664, PMID: 12496757, PMID: 15769891) and 97 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 15769891, ClinVar Variation ID: 3195, ClinVar Variation ID: 21539; PMID: 15860664, ClinVar Variation ID: 929404, ClinVar Variation ID: 3195, ClinVar Variation ID: 265256, PMID: 12496757, ClinVar Variation ID: 3195, ), which increases the likelihood that the c.258+2T>C variant is pathogenic. RT-PCR analysis performed on affected tissue shows evidence of altered splicing of exon 2, with an 8bp deletion, frameshift, and premature protein truncation (PMID: 12496757); in vitro assays suggest that the resulting prematurely truncated protein is unstable (PMID: 17478638). This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function is an established disease mechanism of autosomal recessive Swachman-Diamond syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Swachman-Diamond syndrome. ACMG/AMP Criteria applied: PVS1, PS3_Moderate, PM3_VeryStrong (Richards 2015).
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Suma Genomics, SCV004037087.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | 1 | not provided | not provided | clinical testing | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | not provided | not provided | not provided | 1 | not provided | not provided | not provided | |
From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004805074.2
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | research | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004813118.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (2) |
Description
Variant summary: SBDS c.258+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site and three predict the variant creates/strengthens a cryptic 5' donor site. At least one publication reports experimental evidence that this variant indeed affects mRNA splicing and results in the skipping of exon 2 (e.g. Peretto_2023). The variant allele was found at a frequency of 0.0039 in 251238 control chromosomes in the gnomAD database, including 2 homozygotes. However, due to the presence of a SBDS pseudogene, this frequency may be inaccurate, allowing no conclusion about variant significance. c.258+2T>C has been reported in the literature in many individuals affected with Shwachman-Diamond Syndrome 1 and is considered a common disease variant (e.g. Furutani_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 36835434, 34758064). ClinVar contains an entry for this variant (Variation ID: 3196). Based on the evidence outlined above, the variant was classified as pathogenic.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
Last Updated: May 1, 2024