Submissions for variant NM_152564.5(VPS13B):c.1768G>A (p.Ala590Thr)

gnomAD frequency: 0.00068  dbSNP: rs140601319

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000711291	SCV000225902	uncertain significance	not provided	2014-10-17	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000193331	SCV000249400	uncertain significance	not specified	2015-04-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000711291	SCV000564894	likely benign	not provided	2020-12-16	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17990063, 19006247)
Fulgent Genetics, Fulgent Genetics	RCV000515161	SCV000611527	uncertain significance	Cohen syndrome	2017-05-23	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000711291	SCV000841628	uncertain significance	not provided	2017-09-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002317005	SCV000850435	uncertain significance	Inborn genetic diseases	2019-03-12	criteria provided, single submitter	clinical testing	The p.A590T variant (also known as c.1768G>A), located in coding exon 12 of the VPS13B gene, results from a G to A substitution at nucleotide position 1768. The alanine at codon 590 is replaced by threonine, an amino acid with similar properties. In one study, this alteration was determined to be paternally inherited in a 2 year old individual with clinically suspected Cohen syndrome; however, this individual was not found to carry a second VPS13B alteration (Katzaki E et al. J. Hum. Genet., 2007 Nov;52:1011-7). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000515161	SCV001013994	benign	Cohen syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000515161	SCV001325780	likely benign	Cohen syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Genome-Nilou Lab	RCV000515161	SCV001737255	uncertain significance	Cohen syndrome	2021-05-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000711291	SCV001746048	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	VPS13B: BP4, BP5, BS2
New York Genome Center	RCV000515161	SCV002764303	uncertain significance	Cohen syndrome	2021-06-23	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000711291	SCV004025956	uncertain significance	not provided	2020-09-28	criteria provided, single submitter	clinical testing
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252626	SCV001428387	uncertain significance	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000515161	SCV001456244	benign	Cohen syndrome	2020-01-06	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000711291	SCV001979228	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000711291	SCV001980048	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003416071	SCV004108446	uncertain significance	VPS13B-related disorder	2024-08-06	no assertion criteria provided	clinical testing	The VPS13B c.1768G>A variant is predicted to result in the amino acid substitution p.Ala590Thr. This variant was reported in the heterozygous state in an individual with clinical features of Cohen syndrome (Katzaki et al. 2007. PubMed ID: 17990063). Importantly, a second potentially pathogenic allele was not detected in this individual. This variant was also described as a variant of uncertain significance in a cohort of individuals with Cohen syndrome; however, in vitro functional data indicated that this variant may behave similar to wild type in regards to localization (Zorn et al. 2022. PubMed ID: 35690661). This variant is reported in 0.14% of alleles in individuals of European (Non-Finnish) descent and found in two homozygotes in gnomAD. This frequency is higher than expected for a pathogenic variant. Although we suspect this variant may be benign, at this time its clinical significance is uncertain.