Submissions for variant NM_016038.4(SBDS):c.120del (p.Ser41fs)

dbSNP: rs113993990

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255360	SCV000321932	pathogenic	not provided	2016-06-07	criteria provided, single submitter	clinical testing	The c.120delG pathogenic variant in the SBDS gene has been reported previously (as c.119delG due to alternate nomenclature) in association with Schwachman-Diamond syndrome (Boocock et al., 2003). The c.120delG variant causes a frameshift starting with codon Serine 41, changes this amino acid to an Alanine residue and creates a premature Stop codon at position 18 of the new reading frame, denoted p.Ser41AlafsX18. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.120delG variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.120delG as a pathogenic variant.
Fulgent Genetics, Fulgent Genetics	RCV002503966	SCV002800723	pathogenic	Shwachman-Diamond syndrome 1; Aplastic anemia	2022-04-19	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000020725	SCV003922249	pathogenic	Shwachman-Diamond syndrome 1	2023-05-02	criteria provided, single submitter	curation	The heterozygous p.Ser41AlafsTer18 variant in SBDS was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 3196), in one individual with Swachman-Diamond syndrome. This individual also carried a pathogenic variant (ClinVar Variation ID: 3196), however the phase of these variants are unknown at this time. The p.Ser41AlafsTer18 variant in SBDS has been previously reported in at least 5 unrelated individuals with Swachman-Diamond syndrome (PMID: 31475115, PMID: 17539775, PMID: 24388329, PMID: 14984468) but has been identified in 0.002% (2/113580) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1175585213). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. These 5 previously reported unrelated individuals were compound heterozygotes who carried a reported pathogenic variant in unknown phase (ClinVar Variation ID: 3196, PMID: 31475115, PMID: 17539775, PMID: 24388329, PMID: 14984468), which increases the likelihood that the p.Ser41AlafsTer18 variant in SBDS is pathogenic. This variant has also been reported in ClinVar (Variation ID: 265256) and has been interpreted as pathogenic by GeneDx, Fulgent Genetics, and University of Chicago Genetic Services Laboratory. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 41 and leads to a premature termination codon 18 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the SBDS gene is an established disease mechanism in 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, PM3_Strong, PM2_Supporting (Richards 2015).
Baylor Genetics	RCV003475858	SCV004202341	pathogenic	Aplastic anemia	2023-07-15	criteria provided, single submitter	clinical testing
GeneReviews	RCV000020725	SCV000041298	not provided	Shwachman-Diamond syndrome 1		no assertion provided	literature only
Genetic Services Laboratory, University of Chicago	RCV000255360	SCV003840029	pathogenic	not provided	2022-09-13	no assertion criteria provided	clinical testing	DNA sequence analysis of the SBDS gene demonstrated a one base pair deletion in exon 1, c.120del. This sequence change results in an amino acid frameshift and creates a premature stop codon 18 amino acids downstream of the change, p.Ser41Alafs*18. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated SBDS protein with potentially abnormal function. This sequence change has been described in the gnomAD database in 2 individual which corresponds to a population frequency of 0.0008% ((dbSNP rs1175585213). This pathogenic sequence change has previously been described in individuals with SBDS-related disorders (PMID: 12496757, 24388329). Homozygous or compound heterozygous pathogenic variants in the SBDS gene are associated with Shwachman-Bodian-Diamond Syndrome (SBDS) [OMIM#260400]. Features of SDS include exocrine pancreatic dysfunction, growth failure, skeletal changes and hematologic abnormalities with susceptibility to myelodysplastic syndrome and acute myelogeneous leukemia. One pathogenic variant, c.258+2T>G, has been identified in individuals with aplastic anemia in the heterozygous state (PMID: 17478638). However, further studies are needed to establish the association between heterozygous pathogenic variants in SBDS and aplastic anemia. Clinical correlation is recommended.