Submissions for variant NM_152564.5(VPS13B):c.1594C>T (p.Arg532Trp)

gnomAD frequency: 0.00004  dbSNP: rs369930405

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000516504	SCV000616266	uncertain significance	not specified	2016-08-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001242970	SCV001416096	uncertain significance	Cohen syndrome	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 532 of the VPS13B protein (p.Arg532Trp). This variant is present in population databases (rs369930405, 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: 448874). 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 expected to disrupt VPS13B protein function. 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	RCV001805132	SCV002050529	uncertain significance	not provided	2021-06-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533)
Natera, Inc.	RCV001242970	SCV001454226	uncertain significance	Cohen syndrome	2019-11-11	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004742480	SCV005360565	uncertain significance	VPS13B-related disorder	2024-05-15	no assertion criteria provided	clinical testing	The VPS13B c.1594C>T variant is predicted to result in the amino acid substitution p.Arg532Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.