Submissions for variant NM_152564.5(VPS13B):c.2473G>A (p.Ala825Thr)

gnomAD frequency: 0.00005  dbSNP: rs148788159

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724769	SCV000226662	uncertain significance	not provided	2015-05-05	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000175217	SCV000597880	uncertain significance	not specified	2016-02-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002313040	SCV000848370	uncertain significance	Inborn genetic diseases	2022-03-28	criteria provided, single submitter	clinical testing	The c.2473G>A (p.A825T) alteration is located in exon 17 (coding exon 16) of the VPS13B gene. This alteration results from a G to A substitution at nucleotide position 2473, causing the alanine (A) at amino acid position 825 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000820910	SCV000961647	uncertain significance	Cohen syndrome	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 825 of the VPS13B protein (p.Ala825Thr). This variant is present in population databases (rs148788159, gnomAD 0.02%). 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: 194773). 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. 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.
Illumina Laboratory Services, Illumina	RCV000820910	SCV001325570	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.
New York Genome Center	RCV000820910	SCV002764442	uncertain significance	Cohen syndrome	2021-11-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000820910	SCV002794032	uncertain significance	Cohen syndrome	2021-08-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000724769	SCV004036905	uncertain significance	not provided	2023-09-21	criteria provided, single submitter	clinical testing	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
Breakthrough Genomics, Breakthrough Genomics	RCV000724769	SCV005196052	uncertain significance	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV000820910	SCV001456253	uncertain significance	Cohen syndrome	2020-01-12	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003416075	SCV004116566	uncertain significance	VPS13B-related disorder	2024-04-25	no assertion criteria provided	clinical testing	The VPS13B c.2473G>A variant is predicted to result in the amino acid substitution p.Ala825Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.