ClinVar Miner

Submissions for variant NM_016038.4(SBDS):c.505C>T (p.Arg169Cys)

gnomAD frequency: 0.00001  dbSNP: rs113993996
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
SIB Swiss Institute of Bioinformatics RCV000020731 SCV000787502 uncertain significance Shwachman-Diamond syndrome 1 2018-04-16 criteria provided, single submitter curation This variant is interpreted as a Uncertain Significance, for Shwachman-Diamond syndrome, Autosomal Recessive inheritance. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product.
GeneDx RCV003314555 SCV004014606 likely pathogenic not provided 2024-05-20 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12496757, 15860664, 15701631, 23115272, 21536732, 19602484, 15284109, 20658628, 35982160)
Baylor Genetics RCV003473118 SCV004202332 likely pathogenic Aplastic anemia 2024-01-30 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000020731 SCV005907606 uncertain significance Shwachman-Diamond syndrome 1 2025-02-06 criteria provided, single submitter curation The p.Arg169Cys variant in SBDS has been reported, in the compound heterozygous state, in 1 individual with Shwachman-Diamond syndrome (PMID: 15284109) and has been identified in 0.002% (1/44880) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; (dbSNP rs113993996). 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. The presence of a known pseudogene, SBDSP1, can impact the reliability of allele frequencies. This variant has also been reported in ClinVar (Variation ID: 21541) and has been interpreted as a variant of uncertain significance by SIB Swiss Institute of Bioinformatics and as likely pathogenic by Baylor Genetics and GeneDx. In vitro functional studies provide some evidence that the p.Arg169Cys variant may not impact protein function (PMID: 23115272). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg169Cys variant is uncertain. ACMG/AMP Criteria applied: PM3, BS3_supporting, PP3_moderate, PM2_supporting (Richards 2015).
Department of Pathology and Laboratory Medicine, Sinai Health System RCV005394169 SCV006058638 likely pathogenic Shwachman-Diamond syndrome 1; Aplastic anemia 2022-05-25 criteria provided, single submitter research
GeneReviews RCV000020731 SCV000041306 not provided Shwachman-Diamond syndrome 1 no assertion provided literature only

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