ClinVar Miner

Submissions for variant NM_152564.5(VPS13B):c.436C>T (p.Arg146Ter)

gnomAD frequency: 0.00008  dbSNP: rs144539572
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410784 SCV000485767 likely pathogenic Cohen syndrome 2016-02-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000410784 SCV000920347 pathogenic Cohen syndrome 2021-02-21 criteria provided, single submitter clinical testing Variant summary: VPS13B c.436C>T (p.Arg146X) 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. At-least one truncation downstream of this position has been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2e-05 in 251172 control chromosomes. c.436C>T has been reported in the literature in at-least two individuals affected with Cohen Syndrome, one of whom as a critically ill infant, underwent extensive clinical and diagnostic workup by whole genome sequencing (example, El Chehadeh_2010, Duplomb_2019, Wang_2020). 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. All submitters classified the variant as pathogenic/likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000410784 SCV001391538 pathogenic Cohen syndrome 2023-12-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg146*) 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 (rs144539572, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Cohen syndrome (PMID: 20656880, 23188044). ClinVar contains an entry for this variant (Variation ID: 370440). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab RCV000410784 SCV001822009 pathogenic Cohen syndrome 2021-07-22 criteria provided, single submitter clinical testing
GeneDx RCV002222498 SCV002499980 pathogenic not provided 2022-03-25 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; This variant is associated with the following publications: (PMID: 25525159, 23188044, 20656880, 30843084, 32005694)
Fulgent Genetics, Fulgent Genetics RCV000410784 SCV002807559 likely pathogenic Cohen syndrome 2021-12-06 criteria provided, single submitter clinical testing
Natera, Inc. RCV000410784 SCV002079432 pathogenic Cohen syndrome 2020-03-16 no assertion criteria provided clinical testing

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