VCV000003195.50 - ClinVar

NM_016038.4(SBDS):c.183_184delinsCT (p.Lys62Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(18)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_016038.4(SBDS):c.183_184delinsCT (p.Lys62Ter)

Variation ID: 3195 Accession: VCV000003195.50

Type and length

Indel, 2 bp

Location

Cytogenetic: 7q11.21 7: 66994286-66994287 (GRCh38) [ NCBI UCSC ] 7: 66459273-66459274 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Oct 20, 2024	Apr 16, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_016038.4:c.183_184delTAinsCT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_016038.4:c.183_184delinsCT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_057122.2:p.Lys62Ter	nonsense
NM_016038.3:c.183_184delinsCT
NC_000007.14:g.66994286_66994287delinsAG
NC_000007.13:g.66459273_66459274delinsAG
NG_033069.1:g.2482_2483delinsAG
LRG_104:g.6315_6316delinsCT
LRG_104t1:c.183_184delTAinsCT	LRG_104p1:p.Lys62Ter

... more HGVS ... less HGVS

Protein change

K62*

Other names

Canonical SPDI

NC_000007.14:66994285:TA:AG

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

effect on RNA splicing; Variation Ontology [ VariO:0362]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA340050 OMIM: 607444.0001 dbSNP: rs113993991 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SBDS		-	-	GRCh38 GRCh37	121	142

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Shwachman-Diamond syndrome 1	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	Oct 31, 2023	RCV000003346.31
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Sep 1, 2023	RCV000255938.35
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Mar 21, 2023	RCV000622680.12
Aplastic anemia Shwachman-Diamond syndrome 1	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Aug 23, 2022	RCV002496241.9
SBDS-related disorder	Pathogenic (1)	no assertion criteria provided	May 24, 2024	RCV003904800.2
Shwachman syndrome	Pathogenic (1)	criteria provided, single submitter	Apr 16, 2024	RCV004017224.1
Aplastic anemia	Pathogenic (1)	criteria provided, single submitter	Mar 30, 2024	RCV003472961.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Oct 27, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Shwachman-Diamond syndrome Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000596927.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Pathogenic (Jan 08, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000338913.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SBDS Number of individuals with the variant: 1 Sex: mixed
Pathogenic (Jul 09, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Shwachman-Diamond syndrome 1 Aplastic anemia Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002777651.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Apr 16, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Shwachman syndrome (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000967682.2 First in ClinVar: Aug 26, 2019 Last updated: Apr 20, 2024	Publications: PubMed (15) PubMed: 29375851‚ 12496757‚ 15342903‚ 14749921‚ 15860664‚ 15701631‚ 21695142‚ 22934832‚ 22935661‚ 24388329‚ 24629175‚ 25729736‚ 25844324‚ 26081292‚ 29753700 Comment: The p.Lys62X variant in SBDS is the most common pathogenic variant identified in individuals with Shwachman-Diamond syndrome (Boocock 2003 PMID: 12496757). This variant has also … (more) The p.Lys62X variant in SBDS is the most common pathogenic variant identified in individuals with Shwachman-Diamond syndrome (Boocock 2003 PMID: 12496757). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 3195) and has been identified in 0.1% (69/59956) of Admixed American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0); however, this allele frequency may not be accurate due to the presence of a pseudogene (SBDSP). Note that this variant was documented separately as chr7:66994286T>A and chr7:66994287A>G in gnomAD. This variant usually occurs as the result of a gene conversion event and results in the introduction of a premature termination codon at position 62. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the SBDS gene is an established disease mechanism in Shwachman-Diamond syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Shwachman-Diamond syndrome. ACMG/AMP criteria applied: PVS1, PM3_Very Strong. (less)
Pathogenic (Jul 13, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005198810.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Nov 18, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321933.6 First in ClinVar: Oct 09, 2016 Last updated: Dec 19, 2017	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 14749921, 24388329, 25729736, 32098966, 22934832, 15860664, 22935661, 12496757, 15342903, 25844324, 24629175, 26081292, 29444436, 29892551, 28485484, 29375851, 29753700, 15942154, 16007594, 15474150, 30198570, 17920346, 30105119, 15701631, 21695142, 30894704, 32293785, 31589614) (less)
Pathogenic (Dec 21, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Shwachman-Diamond syndrome 1 Affected status: yes Allele origin: unknown	Baylor Genetics Study: CSER-TexasKidsCanSeq Accession: SCV002096994.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic (Dec 30, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: case-control	Shwachman-Diamond syndrome 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Genetics Laboratory, Department of Biology, Semnan University Accession: SCV002569122.1 First in ClinVar: Sep 10, 2022 Last updated: Sep 10, 2022	Comment: The identified mutation changes the splicing process of SBDS gene. Clinical Features: Exocrine pancreatic insufficiency (present) Age: 0-9 years Sex: male Ethnicity/Population group: Semnan Geographic origin: Iran Method: Genomic DNA was extracted from blood sample of patient and his healthy parents using QIAamp DNA Blood Mini Kit (Germany) according to the manufacturer's instructions. To investigate the genetic cause of the abnormal manifestations reported in the affected patient, Whole-exome sequencing (WES) was used to enrich all exons of the protein-coding genes and a few other important genomic regions. The WES was performed for about 100 million reads, using the Illumina Hiseq2000 sequencer platform and Agilent SureSelect Human All Exon V7 kit (Agilent, Santa Clara, USA). Data filtering was first performed based on frequency and then according to intronic, upstream, downstream, 3'-UTR, 5'-UTR, intergenic and other non-coding variants. At final step, synonymous mutations were also filtered. In general, test platform examined more than 95% of the targeted regions with sensitivity of > 99%. The results of WES were analyzed by bioinformatics tools BWA aligner, GATK, and Annovar and public databases ClinVar, gnomAD, Kaviar, and GME. In addition, ACMG (American College of Medical Genetics) guidelines and local population database (BayanGene) with more than 4000 unrelated individuals were utilized. As control, 250 healthy individuals with the same ethnicity as the studied patient were also screened for the mutation found. Online bioinformatics tools MutationTaster, SIFT, and CADD_phred software were used to predict the likely pathogenic effects of the mutation. To investigate the effect of identified mutation on the SBDS protein in terms of possible structural and functional changes compared to wild-type protein, SMART tool was used. In order to confirm the new mutation found, PCR and Sanger sequencing was performed. Subsequently, Chromas software was applied to analyze the results of Sanger sequencing.
Pathogenic (Aug 23, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aplastic anemia Shwachman-Diamond syndrome 1 Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV003924240.1 First in ClinVar: May 20, 2023 Last updated: May 20, 2023	Comment: This variant is very well described in the literature in association with Shwachman-Diamond syndrome and is one of the most common pathogenic variants in the … (more) This variant is very well described in the literature in association with Shwachman-Diamond syndrome and is one of the most common pathogenic variants in the SBDS gene, most often found in trans with c.258+2T>C (Boocock 2003 PMID:12496757; Shammas 2005 PMID:15701631; Nelson 2018 PMID:20301722). It is present in the Genome Aggregation Database (Highest reported MAF: 0.05% [9/19936]; https://gnomad.broadinstitute.org/variant/7-66459273-T-A?dataset=gnomad_r2_1); please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. It is present in ClinVar, with several laboratories classifying it was pathogenic (Variation ID:3195). This variant creates a premature stop at this codon which results in an abnormal protein, and has been experimentally confirmed to result in a loss of protein function due to impaired cytoplasmic localization in vitro (Shammas 2005 PMID:15701631; Orelio 2011 PMID:21695142). Loss of function is a known mechanism of disease for this gene (Nelson 2018 PMID:20301722). Importantly, this variant has been documented to be present in a highly homologous pseudogene of SBDS, and is often introduced into the functional SBDS gene via a gene conversion event; gene conversion events involving SBDS and its pseudogene (SBDSP1) are a well-documented cause of Shwachman-Diamond syndrome in some individuals (Boocock 2003 PMID:12496757; Nelson 2018 PMID:20301722). In summary, this variant is classified as pathogenic. (less)
Pathogenic (Nov 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001714210.3 First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024	Publications: PubMed (2) PubMed: 32293785‚ 34704233 Comment: PM2_supporting, PS3, PS4, PVS1 Number of individuals with the variant: 2
Pathogenic (Oct 31, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Shwachman-Diamond syndrome 1 Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV004239053.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024	Publications: PubMed (4) PubMed: 12496757‚ 15701631‚ 21695142‚ 35322185 Comment: c.183_184delinsCT is a recurring variant known to cause Shwachman-Diamond syndrome 1 and arises from a gene-conversion event between SBDS and its pseudogene SBDSP1. It has … (more) c.183_184delinsCT is a recurring variant known to cause Shwachman-Diamond syndrome 1 and arises from a gene-conversion event between SBDS and its pseudogene SBDSP1. It has been reported in ClinVar (Variation ID 3195). This nonsense variant results in a premature stop codon in exon 2 of 5, likely leading to nonsense-mediated decay and lack of protein production. We consider c.183_184delinsCT in SBDS to be pathogenic. (less)
Pathogenic (Mar 21, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000740931.4 First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 12496757‚ 15701631‚ 15942154‚ 24388329 Comment: The c.183_184delTAinsCT (p.K62) alteration, located in exon 2 (coding exon 2) of the SBDS gene, consists of an in-frame deletion of TA and insertion of … (more) The c.183_184delTAinsCT (p.K62) alteration, located in exon 2 (coding exon 2) of the SBDS gene, consists of an in-frame deletion of TA and insertion of CT at nucleotide positions 183 to 184. This changes the amino acid at position 62 from a lysine (K) to a stop codon. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation was reported in 82 of 250 disease alleles in a cohort of individuals with Shwachman-Diamond syndrome. In eight of the families studied, this mutation was found as part of a complex allele, c.[183_184delTAinsCT;258+2T>C], in trans with an isolated copy of c.258+2T>C (Boocock, 2003). In another study, this alteration was described compound heterozygous with c.258+2T>C in five individuals who presented with pancreatic insufficiency and failure to thrive; three of those individuals also had persistent neutropenia (Kawakami, 2005). A functional study in yeast cells found that this mutation resulted in complete loss of function (Shammas, 2005). Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Mar 30, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aplastic anemia Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004202328.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Jul 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Shwachman-Diamond syndrome 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002767017.2 First in ClinVar: Dec 24, 2022 Last updated: Jul 23, 2024	Publications: PubMed (1) PubMed: 30413969 Comment: 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 … (more) 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) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition. This variant is present in gnomAD (v3) separately as chr7:66994286T>A and chr7:66994287A>G (both 121 heterozygotes, 0 homozygotes). Based on their pattern of co-occurrence, these variants are likely found on the same haplotype in most individuals in gnomAD. (SP) 0702 - Other NMD-predicted variants comparable to the one identified in this case have strong previous evidence for pathogenicity. There are at least five NMD-predicted variants that have been classified as pathogenic or likely pathogenic (DECIPHER, ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories and is one of the most common pathogenic SBDS variants (ClinVar, GeneReviews, PMID: 30413969). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant, NM_016038.2(SBDS):c.258+2T>C, in a recessive disease. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Sep 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002563952.13 First in ClinVar: Aug 23, 2022 Last updated: Oct 20, 2024	Comment: SBDS: PVS1, PM2 Number of individuals with the variant: 3
Pathogenic (Jul 01, 2005)	no assertion criteria provided Method: literature only	SHWACHMAN-DIAMOND SYNDROME 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023504.4 First in ClinVar: Apr 04, 2013 Last updated: Apr 03, 2021	Publications: PubMed (3) PubMed: 12496757‚ 15769891‚ 32412173 Comment on evidence: In 79 of 141 families with Shwachman-Diamond syndrome (SDS1; 260400) with conversion mutations, Boocock et al. (2003) found that affected individuals were compound heterozygous for … (more) In 79 of 141 families with Shwachman-Diamond syndrome (SDS1; 260400) with conversion mutations, Boocock et al. (2003) found that affected individuals were compound heterozygous for 2 mutations in exon 2 of the SBDS gene: 183-184TA-CT and 258+2T-C (IVS2DS+2T-C; 607444.0002). The dinucleotide alteration 183-184TA-CT introduced an in-frame stop codon (lys62 to ter; K62X). The 258+2T-C mutation was predicted to disrupt the donor splice site of intron 2; it resulted in an 8-bp deletion consistent with use of an upstream cryptic splice donor site at position 251-252. The 258+2T-C and the resultant 8-bp deletion caused premature termination of the encoded protein by frameshift. In 44 families there was compound heterozygosity of 258+2T-C with another allele. In 7 families there was homozygosity for 258+2T-C. No incidence of homozygosity for 183-184TA-CT was observed. In 8 alleles of the SBDS gene found by Boocock et al. (2003) in patients with SDS, both the 183-184TA-CT and the 258+2T-C change were on the same allele. In 11 patients with SDS, Kuijpers et al. (2005) identified compound heterozygosity for the K62X and 258+2T-C mutations in the SBDS gene. By Sanger sequencing in 2 patients with SDS, Yamada et al. (2020) identified compound heterozygous mutations in the SBDS gene: c.183-184TA-CT and c.201A-G on one allele and c.258+2T-C the other allele. However, the c.183-184TA-CT and c.201A-G variants were not identified by whole-exome sequencing in either patient. Yamada et al. (2020) concluded that these variants were missed by whole-exome analysis due to mismapping of reads resulting from the inability to discriminate between SBDS and the SBDSP1 pseudogene. All 3 variants were identified with transcriptome analysis via RNAseq in blood samples from both patients, leading Yamada et al. (2020) to conclude that RNA-seq is an effective assay for the diagnosis of SDS. (less)
Pathogenic (May 24, 2024)	no assertion criteria provided Method: clinical testing	SBDS-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004727084.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The SBDS c.183_184delinsCT variant is predicted to result in premature protein termination (p.Lys62). This variant has been reported in many individuals with Shwachman-Diamond syndrome when … (more) The SBDS c.183_184delinsCT variant is predicted to result in premature protein termination (p.Lys62). This variant has been reported in many individuals with Shwachman-Diamond syndrome when found with another pathogenic variant (see for example Boocock et al. 2003. PubMed ID: 12496757; Myers et al. 2014. PubMed ID: 24388329). This variant is documented separately as c.183T>C and c.184A>T in gnomAD, therefore the reported gnomAD frequency for this variant may not be accurate. Loss-of-function variants in SBDS are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
not provided (-)	no classification provided Method: literature only	Shwachman-Diamond syndrome 1 Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000041300.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: Bookshelf: NBK1756 Bookshelf: NBK1756
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Comment:

The p.Lys62X variant in SBDS is the most common pathogenic variant identified in individuals with Shwachman-Diamond syndrome (Boocock 2003 PMID: 12496757). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 3195) and has been identified in 0.1% (69/59956) of Admixed American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0); however, this allele frequency may not be accurate due to the presence of a pseudogene (SBDSP). Note that this variant was documented separately as chr7:66994286T>A and chr7:66994287A>G in gnomAD. This variant usually occurs as the result of a gene conversion event and results in the introduction of a premature termination codon at position 62. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the SBDS gene is an established disease mechanism in Shwachman-Diamond syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Shwachman-Diamond syndrome. ACMG/AMP criteria applied: PVS1, PM3_Very Strong.

Comment:

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 14749921, 24388329, 25729736, 32098966, 22934832, 15860664, 22935661, 12496757, 15342903, 25844324, 24629175, 26081292, 29444436, 29892551, 28485484, 29375851, 29753700, 15942154, 16007594, 15474150, 30198570, 17920346, 30105119, 15701631, 21695142, 30894704, 32293785, 31589614)

Comment:

This variant is very well described in the literature in association with Shwachman-Diamond syndrome and is one of the most common pathogenic variants in the SBDS gene, most often found in trans with c.258+2T>C (Boocock 2003 PMID:12496757; Shammas 2005 PMID:15701631; Nelson 2018 PMID:20301722). It is present in the Genome Aggregation Database (Highest reported MAF: 0.05% [9/19936]; https://gnomad.broadinstitute.org/variant/7-66459273-T-A?dataset=gnomad_r2_1); please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. It is present in ClinVar, with several laboratories classifying it was pathogenic (Variation ID:3195). This variant creates a premature stop at this codon which results in an abnormal protein, and has been experimentally confirmed to result in a loss of protein function due to impaired cytoplasmic localization in vitro (Shammas 2005 PMID:15701631; Orelio 2011 PMID:21695142). Loss of function is a known mechanism of disease for this gene (Nelson 2018 PMID:20301722). Importantly, this variant has been documented to be present in a highly homologous pseudogene of SBDS, and is often introduced into the functional SBDS gene via a gene conversion event; gene conversion events involving SBDS and its pseudogene (SBDSP1) are a well-documented cause of Shwachman-Diamond syndrome in some individuals (Boocock 2003 PMID:12496757; Nelson 2018 PMID:20301722). In summary, this variant is classified as pathogenic.

Comment:

c.183_184delinsCT is a recurring variant known to cause Shwachman-Diamond syndrome 1 and arises from a gene-conversion event between SBDS and its pseudogene SBDSP1. It has been reported in ClinVar (Variation ID 3195). This nonsense variant results in a premature stop codon in exon 2 of 5, likely leading to nonsense-mediated decay and lack of protein production. We consider c.183_184delinsCT in SBDS to be pathogenic.

Comment:

The c.183_184delTAinsCT (p.K62*) alteration, located in exon 2 (coding exon 2) of the SBDS gene, consists of an in-frame deletion of TA and insertion of CT at nucleotide positions 183 to 184. This changes the amino acid at position 62 from a lysine (K) to a stop codon. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation was reported in 82 of 250 disease alleles in a cohort of individuals with Shwachman-Diamond syndrome. In eight of the families studied, this mutation was found as part of a complex allele, c.[183_184delTAinsCT;258+2T>C], in trans with an isolated copy of c.258+2T>C (Boocock, 2003). In another study, this alteration was described compound heterozygous with c.258+2T>C in five individuals who presented with pancreatic insufficiency and failure to thrive; three of those individuals also had persistent neutropenia (Kawakami, 2005). A functional study in yeast cells found that this mutation resulted in complete loss of function (Shammas, 2005). Based on the available evidence, this alteration is classified as pathogenic.

Comment:

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) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition. This variant is present in gnomAD (v3) separately as chr7:66994286T>A and chr7:66994287A>G (both 121 heterozygotes, 0 homozygotes). Based on their pattern of co-occurrence, these variants are likely found on the same haplotype in most individuals in gnomAD. (SP) 0702 - Other NMD-predicted variants comparable to the one identified in this case have strong previous evidence for pathogenicity. There are at least five NMD-predicted variants that have been classified as pathogenic or likely pathogenic (DECIPHER, ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories and is one of the most common pathogenic SBDS variants (ClinVar, GeneReviews, PMID: 30413969). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant, NM_016038.2(SBDS):c.258+2T>C, in a recessive disease. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

The SBDS c.183_184delinsCT variant is predicted to result in premature protein termination (p.Lys62*). This variant has been reported in many individuals with Shwachman-Diamond syndrome when found with another pathogenic variant (see for example Boocock et al. 2003. PubMed ID: 12496757; Myers et al. 2014. PubMed ID: 24388329). This variant is documented separately as c.183T>C and c.184A>T in gnomAD, therefore the reported gnomAD frequency for this variant may not be accurate. Loss-of-function variants in SBDS are expected to be pathogenic. This variant is interpreted as pathogenic.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
effect on RNA splicing (VariO:0362)			Genetics Laboratory, Department of Biology, Semnan University Accession: SCV002569122.1

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Shwachman-Diamond Syndrome.	Adam MP	-	2024	PMID: 20301722
Shwachman Diamond syndrome: narrow genotypic spectrum and variable clinical features.	Thompson AS	Pediatric research	2022	PMID: 35322185
Identification of an asymptomatic Shwachman-Bodian-Diamond syndrome mutation in a patient with acute myeloid leukemia.	Shibata S	International journal of hematology	2022	PMID: 34704233
Shortfall of exome analysis for diagnosis of Shwachman-Diamond syndrome: Mismapping due to the pseudogene SBDSP1.	Yamada M	American journal of medical genetics. Part A	2020	PMID: 32412173
Inflammatory manifestations in patients with Shwachman-Diamond syndrome: A novel phenotype.	Furutani E	American journal of medical genetics. Part A	2020	PMID: 32293785
Shwachman-Diamond Syndrome: Molecular Mechanisms and Current Perspectives.	Bezzerri V	Molecular diagnosis & therapy	2019	PMID: 30413969
Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort.	Waszak SM	The Lancet. Oncology	2018	PMID: 29753700
Association of isochromosome (7)(q10) in Shwachman-Diamond syndrome with the severity of cytopenia.	Shimosato Y	Clinical case reports	2017	PMID: 29375851
Shwachman-Diamond syndrome (SDS) in a preterm neonate.	Saito-Benz M	Journal of paediatrics and child health	2015	PMID: 26081292
Diffuse alterations in grey and white matter associated with cognitive impairment in Shwachman-Diamond syndrome: evidence from a multimodal approach.	Perobelli S	NeuroImage. Clinical	2015	PMID: 25844324
Two cases of Shwachman-Diamond syndrome in adolescents confirmed by genetic analysis.	Cho WK	Annals of laboratory medicine	2015	PMID: 25729736
Young-age-onset pancreatoduodenal carcinoma in Shwachman-Diamond syndrome.	Nakaya T	Pathology international	2014	PMID: 24629175
Variable clinical presentation of Shwachman-Diamond syndrome: update from the North American Shwachman-Diamond Syndrome Registry.	Myers KC	The Journal of pediatrics	2014	PMID: 24388329
Shwachman-Diamond syndrome: diarrhea, no longer required?	Andolina JR	Journal of pediatric hematology/oncology	2013	PMID: 22935661
Acquired copy number neutral loss of heterozygosity of chromosome 7 associated with clonal haematopoiesis in a patient with Shwachman-Diamond syndrome.	Parikh S	British journal of haematology	2012	PMID: 22934832
Altered intracellular localization and mobility of SBDS protein upon mutation in Shwachman-Diamond syndrome.	Orelio C	PloS one	2011	PMID: 21695142
Clinical and genetic analyses of presumed Shwachman-Diamond syndrome in Japan.	Taneichi H	International journal of hematology	2006	PMID: 16867904
Genetic analysis of Shwachman-Diamond syndrome: phenotypic heterogeneity in patients carrying identical SBDS mutations.	Kawakami T	The Tohoku journal of experimental medicine	2005	PMID: 15942154
The Shwachman-Diamond SBDS protein localizes to the nucleolus.	Austin KM	Blood	2005	PMID: 15860664
Hematologic abnormalities in Shwachman Diamond syndrome: lack of genotype-phenotype relationship.	Kuijpers TW	Blood	2005	PMID: 15769891
Structural and mutational analysis of the SBDS protein family. Insight into the leukemia-associated Shwachman-Diamond Syndrome.	Shammas C	The Journal of biological chemistry	2005	PMID: 15701631
Congenital aplastic anemia caused by mutations in the SBDS gene: a rare presentation of Shwachman-Diamond syndrome.	Kuijpers TW	Pediatrics	2004	PMID: 15342903
Mutations of the SBDS gene are present in most patients with Shwachman-Diamond syndrome.	Woloszynek JR	Blood	2004	PMID: 15284109
Novel SBDS mutations caused by gene conversion in Japanese patients with Shwachman-Diamond syndrome.	Nakashima E	Human genetics	2004	PMID: 14749921
Mutations in SBDS are associated with Shwachman-Diamond syndrome.	Boocock GR	Nature genetics	2003	PMID: 12496757
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SBDS	-	-	-	-
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Text-mined citations for rs113993991 ...

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Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_016038.4(SBDS):c.183_184delinsCT (p.Lys62Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs113993991 ...