Submissions for variant NM_152564.5(VPS13B):c.2911C>T (p.Arg971Ter)

gnomAD frequency: 0.00001  dbSNP: rs120074152

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000002957	SCV000700150	pathogenic	Cohen syndrome	2017-01-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000624804	SCV000742912	pathogenic	Inborn genetic diseases	2017-10-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000002957	SCV001390259	pathogenic	Cohen syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg971*) 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). This variant is present in population databases (rs120074152, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Cohen syndrome (PMID: 15154116). ClinVar contains an entry for this variant (Variation ID: 2823). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000002957	SCV001572475	pathogenic	Cohen syndrome	2021-04-09	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.2911C>T (p.Arg971X) 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 4e-06 in 251120 control chromosomes. c.2911C>T has been reported in the literature in homozygous and compound heterozygous individuals affected with Cohen Syndrome (e.g. Hennies_2004, Seifert_2008, Duplomb_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000002957	SCV002020872	pathogenic	Cohen syndrome	2022-07-11	criteria provided, single submitter	clinical testing
GeneDx	RCV004786234	SCV005401372	pathogenic	not provided	2024-05-08	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30843084, 26104215, 22382802, 21418059, 35898454, 36368352, 15154116, 32384097)
Fulgent Genetics, Fulgent Genetics	RCV000002957	SCV005672018	pathogenic	Cohen syndrome	2024-03-12	criteria provided, single submitter	clinical testing
OMIM	RCV000002957	SCV000023115	pathogenic	Cohen syndrome	2004-07-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000002957	SCV002079537	pathogenic	Cohen syndrome	2021-10-12	no assertion criteria provided	clinical testing