Submissions for variant NM_152564.5(VPS13B):c.9592C>T (p.Arg3198Trp)

gnomAD frequency: 0.00511  dbSNP: rs149842139

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000081924	SCV000113859	benign	not specified	2013-10-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000081924	SCV000249428	likely benign	not specified	2015-06-30	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000081924	SCV000616280	benign	not specified	2024-12-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000531326	SCV000630897	benign	Cohen syndrome	2025-02-02	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000531326	SCV000743197	likely benign	Cohen syndrome	2016-11-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002313813	SCV000848409	benign	Inborn genetic diseases	2018-07-19	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV000531326	SCV000883057	likely benign	Cohen syndrome	2022-05-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000710111	SCV000892864	likely benign	not provided	2024-09-01	criteria provided, single submitter	clinical testing	VPS13B: BP4, BS2
Illumina Laboratory Services, Illumina	RCV000531326	SCV001326316	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx	RCV000710111	SCV001949031	benign	not provided	2020-05-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25502226, 29706646)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000081924	SCV002547502	benign	not specified	2022-05-04	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.9667C>T (p.Arg3223Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0036 in 250822 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 1.44 fold of the estimated maximal expected allele frequency for a pathogenic variant in VPS13B causing Cohen Syndrome phenotype (0.0025), strongly suggesting that the variant is benign. To our knowledge, no penetrant association of c.9667C>T in individuals affected with Cohen Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Breakthrough Genomics, Breakthrough Genomics	RCV000710111	SCV005223976	likely benign	not provided		criteria provided, single submitter	not provided
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000531326	SCV000734591	likely benign	Cohen syndrome		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000710111	SCV001922535	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000531326	SCV002082718	benign	Cohen syndrome	2019-10-18	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003905065	SCV004732083	likely benign	VPS13B-related disorder	2019-03-25	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).