Submissions for variant NM_152564.5(VPS13B):c.5220G>T (p.Glu1740Asp)

gnomAD frequency: 0.00001  dbSNP: rs780598553

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000988101	SCV001137684	pathogenic	Cohen syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000988101	SCV002060139	uncertain significance	Cohen syndrome	2021-11-08	criteria provided, single submitter	clinical testing	NM_017890.4(VPS13B):c.5295G>T(E1765D) is a missense variant classified as a variant of uncertain significance in the context of Cohen syndrome. E1765D been observed in cases with relevant disease (PMID: 22700954). Functional assessments of this variant are not available in the literature. E1765D has been observed in population frequency databases (gnomAD: AFR 0.01%). In summary, there is insufficient evidence to classify NM_017890.4(VPS13B):c.5295G>T(E1765D) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000988101	SCV003440762	uncertain significance	Cohen syndrome	2022-08-20	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 1765 of the VPS13B protein (p.Glu1765Asp). This variant also falls at the last nucleotide of exon 33, which is part of the consensus splice site for this exon. This variant is present in population databases (rs780598553, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of Cohen syndrome (PMID: 22700954). ClinVar contains an entry for this variant (Variation ID: 802428). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV000988101	SCV003816576	likely pathogenic	Cohen syndrome	2022-01-07	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000988101	SCV004046463	uncertain significance	Cohen syndrome	2023-01-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526055	SCV005039496	uncertain significance	not specified	2024-03-12	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.5295G>T (p.Glu1765Asp) results in a conservative amino acid change of the encoded protein in the last nucleotide of exon 33 adjacent to the exon 33 / intron 33 splice donor site. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes or weakens a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250934 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5295G>T has been reported in the literature in multiple individuals in a large consanguineous family affected with Cohen Syndrome with unspecified genotypes (e.g. Dixon-Salazar_2015). This report does not provide unequivocal conclusions about association of the variant with Cohen Syndrome. 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: 22700954). ClinVar contains an entry for this variant (Variation ID: 802428). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.