ClinVar

Description

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).