Submissions for variant NM_152564.5(VPS13B):c.2075G>A (p.Arg692Gln)

gnomAD frequency: 0.00006  dbSNP: rs371500701

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000513467	SCV000226341	uncertain significance	not provided	2017-01-10	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000193499	SCV000249403	uncertain significance	not specified	2015-05-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000513467	SCV000609315	uncertain significance	not provided	2017-05-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001047823	SCV001211805	uncertain significance	Cohen syndrome	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 692 of the VPS13B protein (p.Arg692Gln). This variant is present in population databases (rs371500701, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with VPS13B-related conditions. ClinVar contains an entry for this variant (Variation ID: 194549). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt VPS13B protein function with a negative predictive value of 80%. 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.
GeneDx	RCV000513467	SCV002549358	uncertain significance	not provided	2022-07-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002415747	SCV002729812	uncertain significance	Inborn genetic diseases	2018-08-04	criteria provided, single submitter	clinical testing	The p.R692Q variant (also known as c.2075G>A), located in coding exon 14 of the VPS13B gene, results from a G to A substitution at nucleotide position 2075. The arginine at codon 692 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV001047823	SCV001456248	uncertain significance	Cohen syndrome	2020-04-15	no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV001047823	SCV001749838	not provided	Cohen syndrome		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 12-03-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
PreventionGenetics, part of Exact Sciences	RCV004742311	SCV005351145	uncertain significance	VPS13B-related disorder	2024-03-05	no assertion criteria provided	clinical testing	The VPS13B c.2075G>A variant is predicted to result in the amino acid substitution p.Arg692Gln. This variant has been reported at a frequency of ~0.01% in individuals of European origin in a large population database and has been reported in ClinVar as uncertain (https://www.ncbi.nlm.nih.gov/clinvar). Based on these observations, the c.2075G>A variant is classified as uncertain.