Submissions for variant NM_016038.4(SBDS):c.184A>T (p.Lys62Ter)

gnomAD frequency: 0.00099  dbSNP: rs120074160

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523697	SCV000616861	pathogenic	not provided	2017-07-10	criteria provided, single submitter	clinical testing	The K62X variant in the SBDS gene has been reported previously in an individual with Shwachman-Diamond syndrome who also harbored the c.258+2 T>C variant on the other SBDS allele (Pronicka et al., 2016). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Functional studies demonstrate that the K62X variant results in abnormally low cytoplasmic protein levels and loss of protein function (Orelio et al., 2011; Shammas et al., 2005). The K62X variant is not observed in large population cohorts (Lek et al., 2016). Historically this variant as been reported as c.183_184delTAinsCT. This event is derived from a recombination event with a known psuedogene carrying this variant.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626934	SCV000747637	likely pathogenic	Short stature; Deeply set eye; Agenesis of permanent teeth; Microcephaly; Splenomegaly	2017-01-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000987895	SCV001137385	likely pathogenic	Shwachman-Diamond syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000523697	SCV001446841	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001293358	SCV001481812	pathogenic	Intellectual disability	2021-02-25	criteria provided, single submitter	clinical testing	The variant chr7-66459273-T-A, SBDS(NM_016038.4):c.184A>T,p.(Lys62*) was identified in an individual with NDD. Inheritance was paternal (heterozygous). The variant was reviewed according to current ACMG recommendations and classified as Pathogenic (criteria: PSV1_VeryStrong, PM2_Supporting, PS3_Moderate, PM3_Moderate). This variant was identified in a compound heterozygous state with the variant NM_016038.4(SBDS):c.258+2T>C (Variation ID: 3196).
Revvity Omics, Revvity	RCV000987895	SCV002019991	pathogenic	Shwachman-Diamond syndrome 1	2021-09-25	criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000987895	SCV002073334	pathogenic	Shwachman-Diamond syndrome 1		criteria provided, single submitter	clinical testing	The stop gained p.K62* in SBDS (NM_016038.4) has been previously reported as c.183_184delinsCT. It is known to occur both in cis with 258+2T>C as a complex allele due to gene conversion as well as in trans with c.258+2T>C. The variant is one amongst the three common pathogenic variants, all arising due to gene conversion with the highly homologous pseudogene SBDSP (Nelson AS et al,2018). This variant is predicted to cause loss of normal protein function through protein truncation. Functional studies demonstrate loss of function (Orelio et al,2011). The variant has been submitted to ClinVar as Pathogenic. For these reasons, this variant has been classified as Pathogenic.
Bioinformatics Unit, Institut Pasteur de Montevideo	RCV000987895	SCV002505972	pathogenic	Shwachman-Diamond syndrome 1	2022-05-03	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000987895	SCV004175673	pathogenic	Shwachman-Diamond syndrome 1	2022-09-12	criteria provided, single submitter	clinical testing	The SBDS c.184A>T variant is classified as PATHOGENIC (PVS1, PS3, PS4, PM3) The SBDS c.184A>T variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 62 (PVS1). This variant has been reported many times in conjunction with a second pathogenic variant (NM_016038.4(SBDS):c.258+2T>C) in association with Shwachman-Diamond syndrome (PS4), as is the case with this patient (PM3). Functional studies have shown this variant affects the protein's cellular localisation and motility (PMID:21695142) (PS3). The variant has been reported in dbSNP (rs120074160) and in the HGMD database: CP035464. It has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 449095).
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000523697	SCV001800138	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000523697	SCV001807443	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000523697	SCV001955842	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000523697	SCV001973220	pathogenic	not provided		no assertion criteria provided	clinical testing