Submissions for variant NM_152564.5(VPS13B):c.3348_3349del (p.Cys1117fs)

dbSNP: rs180177327

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Myriad Genetics, Inc.	RCV000002952	SCV001193859	pathogenic	Cohen syndrome	2019-12-09	criteria provided, single submitter	clinical testing	NM_017890.4(VPS13B):c.3348_3349delCT(C1117Ffs*8) is classified as pathogenic in the context of Cohen syndrome. Sources cited for classification include the following: PMID 12730828 and 15141358. Classification of NM_017890.4(VPS13B):c.3348_3349delCT(C1117Ffs*8) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen	RCV000058939	SCV001247882	pathogenic	not provided	2019-10-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000002952	SCV001554547	pathogenic	Cohen syndrome	2021-03-17	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.3348_3349delCT (p.Cys1117PhefsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00023 in 251260 control chromosomes. c.3348_3349delCT has been reported in the literature as a recurrent Finnish founder variant in multiple individuals affected with Cohen Syndrome (Kolehmainen_2003) and has been subsequently cited by others in the field (example, Enomoto_2020, Kondo_2005, Lou_2020, Nasser_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000002952	SCV002179187	pathogenic	Cohen syndrome	2023-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys1117Phefs*8) in the VPS13B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in VPS13B are known to be pathogenic (PMID: 15141358, 16648375, 20461111). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 2818). This premature translational stop signal has been observed in individual(s) with Cohen syndrome (PMID: 12730828, 15141358). This variant is present in population databases (rs774683328, gnomAD 0.3%).
Genetics and Molecular Pathology, SA Pathology	RCV000002952	SCV004175630	pathogenic	Cohen syndrome	2023-04-26	criteria provided, single submitter	clinical testing
OMIM	RCV000002952	SCV000023110	pathogenic	Cohen syndrome	2003-06-01	no assertion criteria provided	literature only
SNPedia	RCV000058939	SCV000090460	not provided	not provided		no assertion provided	not provided
GeneReviews	RCV000002952	SCV000297975	not provided	Cohen syndrome		no assertion provided	literature only
Natera, Inc.	RCV000002952	SCV002079557	pathogenic	Cohen syndrome	2020-06-09	no assertion criteria provided	clinical testing