Submissions for variant NM_152564.5(VPS13B):c.8622-9A>G

dbSNP: rs386834116

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000412777	SCV000491142	likely pathogenic	not provided	2024-07-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 22855652)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000050110	SCV002286337	likely pathogenic	Cohen syndrome	2022-08-05	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with Cohen syndrome (PMID: 22855652). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs386834116, gnomAD 0.003%). This sequence change falls in intron 47 of the VPS13B gene. It does not directly change the encoded amino acid sequence of the VPS13B protein. ClinVar contains an entry for this variant (Variation ID: 56697). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000050110	SCV003845127	pathogenic	Cohen syndrome	2023-02-03	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.8697-9A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic 3' acceptor site eight nucleotides upstream into intron 47. Two predict the variant abolishes the canonical 3' acceptor site and one predicts the variant weakens the canonical 3' acceptor site. This impact on splicing was confirmed via cDNA sequencing by Athanasakis_2012. The variant allele was found at a frequency of 4e-06 in 250926 control chromosomes (gnomAD). c.8697-9A>G has been reported in the literature in at least one compound heterozygous individuals affected with Cohen Syndrome (Athanasakis_2012). These data do not allow any conclusion about variant significance. Two ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000050110	SCV000082519	probable-pathogenic	Cohen syndrome		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.