Submissions for variant NM_152564.5(VPS13B):c.4336C>T (p.Arg1446Ter)

gnomAD frequency: 0.00001  dbSNP: rs386834086

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000050077	SCV000485837	likely pathogenic	Cohen syndrome	2016-02-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000050077	SCV000699446	likely pathogenic	Cohen syndrome	2022-03-21	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.4411C>T (p.Arg1471X) 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 2.4e-05 in 251262 control chromosomes (gnomAD). c.4411C>T has been reported in the literature in at-least one individual affected with Cohen Syndrome (Seifert_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV001804786	SCV002050562	pathogenic	not provided	2021-12-28	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 (Lek et al., 2016); Observed in an individual with Cohen syndrome in published literature (Seifert et al., 2009); additional clinical details were not provided; This variant is associated with the following publications: (PMID: 25525159, 19006247)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000050077	SCV002232112	pathogenic	Cohen syndrome	2023-11-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1471*) 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 (rs386834086, gnomAD 0.006%). 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: 56664). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000050077	SCV003922262	likely pathogenic	Cohen syndrome	2023-05-02	criteria provided, single submitter	curation	The homozygous p.Arg1471Ter variant in VPS13B was identified by our study in one individual with Cohen syndrome. The p.Arg1471Ter variant in VPS13B has been previously reported in one individual with Cohen syndrome (PMID: 19006247) but has been identified in 0.005% (7/128976) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs386834086). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 56664) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This nonsense variant leads to a premature termination codon at position 1471, which is predicted to lead to a truncated or absent protein. Loss of function of the VPS13B gene is an established disease mechanism in autosomal recessive Cohen syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive Cohen syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting (Richards 2015).
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000050077	SCV000082486	probable-pathogenic	Cohen syndrome		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
Natera, Inc.	RCV000050077	SCV002082542	likely pathogenic	Cohen syndrome	2020-09-03	no assertion criteria provided	clinical testing