Submissions for variant NM_152564.5(VPS13B):c.10565C>T (p.Thr3522Ile)

gnomAD frequency: 0.00003  dbSNP: rs781253026

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000407798	SCV000470854	uncertain significance	Cohen syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000407798	SCV001540429	uncertain significance	Cohen syndrome	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with isoleucine at codon 3547 of the VPS13B protein (p.Thr3547Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs781253026, gnomAD 0.009%). 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: 361091). 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.
Natera, Inc.	RCV000407798	SCV002082748	uncertain significance	Cohen syndrome	2019-11-11	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003401376	SCV004110806	uncertain significance	VPS13B-related disorder	2024-05-20	no assertion criteria provided	clinical testing	The VPS13B c.10565C>T variant is predicted to result in the amino acid substitution p.Thr3522Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0085% 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.