Submissions for variant NM_152564.5(VPS13B):c.8440C>T (p.Arg2814Ter)

gnomAD frequency: 0.00002  dbSNP: rs386834113

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000050107	SCV000220706	likely pathogenic	Cohen syndrome	2014-09-17	criteria provided, single submitter	literature only
GeneDx	RCV000579214	SCV000680675	pathogenic	not provided	2022-04-01	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 19006247, 23188044, 24334764, 30843084, 25525159, 31589614, 21865173)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000050107	SCV000918352	pathogenic	Cohen syndrome	2018-07-09	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.8515C>T (p.Arg2839X) 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 (e.g., p.Trp3649X and p.Pro3969fsX41). The variant allele was found at a frequency of 2e-05 in 245746 control chromosomes. c.8515C>T has been reported as a homozygous allele in the literature in individuals affected with Cohen Syndrome, indicating the variant is likely to be associated with disease. At least one publication reports experimental evidence showing a reduction of COH1 mRNA expression (10%-<30% of normal expression) and fragmented Golgi structures in patient cells (Seifert_2011). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000050107	SCV001212421	pathogenic	Cohen syndrome	2023-11-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2839*) 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 (rs386834113, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Cohen syndrome (PMID: 19006247). ClinVar contains an entry for this variant (Variation ID: 56694). For these reasons, this variant has been classified as Pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000050107	SCV000082516	probable-pathogenic	Cohen syndrome		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
Natera, Inc.	RCV000050107	SCV002082680	pathogenic	Cohen syndrome	2021-02-17	no assertion criteria provided	clinical testing