Submissions for variant NM_152564.5(VPS13B):c.11673_11674del (p.Ala3892fs)

dbSNP: rs1180933570

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001231742	SCV001404274	pathogenic	Cohen syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala3917Thrfs*21) in the VPS13B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 106 amino acid(s) of the VPS13B protein. This variant is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 25472526). ClinVar contains an entry for this variant (Variation ID: 958553). This variant disrupts a region of the VPS13B protein in which other variant(s) (p.Asn3954Lysfs*60) have been determined to be pathogenic (PMID: 20656880). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001788428	SCV002031092	likely pathogenic	not provided	2021-11-29	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 106 amino acids are replaced with 20 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25472526)
Myriad Genetics, Inc.	RCV001231742	SCV002060019	uncertain significance	Cohen syndrome	2021-11-08	criteria provided, single submitter	clinical testing	NM_017890.4(VPS13B):c.11748_11749delTG(A3917Tfs*21) is a frameshifting truncation variant classified as a variant of uncertain significance in the context of Cohen syndrome. A3917Tfs*21 has been observed in cases with relevant disease (PMID: 25472526). Functional assessments of this variant are not available in the literature. A3917Tfs*21 has been observed in population frequency databases (gnomAD: AMR 0.003%). In summary, there is insufficient evidence to classify NM_017890.4(VPS13B):c.11748_11749delTG(A3917Tfs*21) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001231742	SCV003923115	likely pathogenic	Cohen syndrome	2023-03-15	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.11748_11749delTG (p.Ala3917ThrfsX21) 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 8e-06 in 251454 control chromosomes. c.11748_11749delTG has been reported in the literature in an individual affected with Cohen Syndrome (Zhao_2015), and they were reported as compound heterozygous with another pathogenic variant. These data suggest the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic (n=3) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Natera, Inc.	RCV001231742	SCV002082812	pathogenic	Cohen syndrome	2020-02-14	no assertion criteria provided	clinical testing