Submissions for variant NM_016038.4(SBDS):c.127G>T (p.Val43Leu)

gnomAD frequency: 0.00096  dbSNP: rs147652512

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001354457	SCV000514462	uncertain significance	not provided	2023-04-24	criteria provided, single submitter	clinical testing	Observed in the heterozygous state with no second SBDS variant in patients with refractory cytopenia or suspected Shwachman-Diamond syndrome (Karow A et al., 2010; Thomassen JC et al., 2016; Rother C et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26136524, 31839986, 34151701, 19951977, 36835434)
Mayo Clinic Laboratories, Mayo Clinic	RCV001354457	SCV001714211	uncertain significance	not provided	2021-03-19	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001821161	SCV002069912	likely benign	not specified	2020-08-09	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354457	SCV001549076	uncertain significance	not provided		no assertion criteria provided	clinical testing	The SBDS p.Val43Leu variant was identified in 1 of 240 proband chromosomes (frequency: 0.0042) from individuals with primary hypocellular refractory cytopenia (Karow_2010_PMID:19951977). The variant was also reported as a heterozygous variant in a girl with cystic fibrosis and Shwachman-Bodian-Diamond Syndrome as a variant of unknown clinical significance (Thomassen_2016). The variant was identified in dbSNP (ID: rs147652512) LOVD 3.0 and ClinVar (classified as likely benign by GeneDx). The variant was identified in control databases in 302 of 268098 chromosomes (1 homozygous) at a frequency of 0.001126 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 254 of 118020 chromosomes (freq: 0.002152), Other in 8 of 6704 chromosomes (freq: 0.001193), European (Finnish) in 16 of 25094 chromosomes (freq: 0.000638), Latino in 15 of 35098 chromosomes (freq: 0.000427), African in 4 of 23554 chromosomes (freq: 0.00017), East Asian in 3 of 19246 chromosomes (freq: 0.000156) and South Asian in 2 of 30526 chromosomes (freq: 0.000066), but was not observed in the Ashkenazi Jewish population. The p.Val43 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The p.Val43Leu variant occurs in the second last base of the exon; this position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing. Further, transcriptional studies did not reveal an effect on splicing due to this variant (Karow_2010_PMID:19951977). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.