Submissions for variant NM_152564.5(VPS13B):c.328C>T (p.Arg110Cys)

gnomAD frequency: 0.00001  dbSNP: rs368290618

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001248478	SCV001421966	uncertain significance	Cohen syndrome	2022-08-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 110 of the VPS13B protein (p.Arg110Cys). This variant is present in population databases (rs368290618, 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: 972443). 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: "Probably Damaging"; Align-GVGD: "Not Available"). 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.
Breakthrough Genomics, Breakthrough Genomics	RCV004692343	SCV005196049	uncertain significance	not provided		criteria provided, single submitter	not provided
GeneDx	RCV004692343	SCV005377834	uncertain significance	not provided	2023-12-13	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001248478	SCV005402367	uncertain significance	Cohen syndrome	2024-05-07	criteria provided, single submitter	clinical testing	The VPS13B c.328C>T (p.Arg110Cys) missense change has a maximum subpopulation frequency of 0.012% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with Cohen syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Natera, Inc.	RCV001248478	SCV002079428	uncertain significance	Cohen syndrome	2020-05-27	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004743367	SCV005364330	uncertain significance	VPS13B-related disorder	2024-04-24	no assertion criteria provided	clinical testing	The VPS13B c.328C>T variant is predicted to result in the amino acid substitution p.Arg110Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.