Submissions for variant NM_152564.5(VPS13B):c.5259dup (p.Gly1754fs)

gnomAD frequency: 0.00002  dbSNP: rs786204533

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169235	SCV000220507	likely pathogenic	Cohen syndrome	2014-07-11	criteria provided, single submitter	literature only
GeneDx	RCV001567222	SCV001790870	pathogenic	not provided	2021-04-07	criteria provided, single submitter	clinical testing	Frameshift 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; Reported in a patient with Cohen syndrome who also harbored an intragenic deletion of exon 31 in the literature (Aradhya et al., 2012), but it is not known whether these variants occurred on the same (in cis) or opposite (in trans) alleles; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22382802)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169235	SCV002202781	pathogenic	Cohen syndrome	2024-02-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly1779Trpfs*5) 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 (rs762691090, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with VPS13B-related conditions. ClinVar contains an entry for this variant (Variation ID: 188881). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169235	SCV002570901	pathogenic	Cohen syndrome	2024-06-12	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.5334dupT (p.Gly1779TrpfsX5) 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. The variant was absent in 250628 control chromosomes. c.5334dupT has been reported in the literature in at least one compound heterozygous individual affected with Cohen Syndrome (Aradhya_2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 22382802). ClinVar contains an entry for this variant (Variation ID: 188881). Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004742302	SCV005360812	likely pathogenic	VPS13B-related disorder	2024-07-29	no assertion criteria provided	clinical testing	The VPS13B c.5259dupT variant is predicted to result in a frameshift and premature protein termination (p.Gly1754Trpfs*5). This variant, also known as c.5334dupT in an alternate transcript, was reported in the compound heterozygous state in an individual with Cohen syndrome (Figure 2 and Supplementary Table 2, Aradhya S et al 2012. PubMed ID: 22382802). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in VPS13B are expected to be pathogenic. This variant is interpreted as likely pathogenic.