Submissions for variant NM_152564.5(VPS13B):c.7678G>A (p.Glu2560Lys)

gnomAD frequency: 0.00304  dbSNP: rs111751379

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000081914	SCV000113849	benign	not specified	2012-10-11	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000081914	SCV000249420	likely benign	not specified	2016-12-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000081914	SCV000316202	likely benign	not specified		criteria provided, single submitter	clinical testing
GeneDx	RCV000081914	SCV000512679	likely benign	not specified	2016-05-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000513903	SCV000611049	likely benign	not provided	2017-03-17	criteria provided, single submitter	clinical testing
Invitae	RCV000547888	SCV000630887	benign	Cohen syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000513903	SCV000841644	likely benign	not provided	2017-12-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002313810	SCV000848643	likely benign	Inborn genetic diseases	2019-05-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000547888	SCV000899085	benign	Cohen syndrome	2023-12-04	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, Institute for Ophthalmic Research	RCV001199598	SCV001162769	benign	Retinitis pigmentosa	2023-12-12	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV000547888	SCV001324016	likely benign	Cohen syndrome	2018-01-12	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.
Genome-Nilou Lab	RCV000547888	SCV001653379	likely benign	Cohen syndrome	2021-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000081914	SCV003844718	benign	not specified	2023-02-14	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.7753G>A (p.Glu2585Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0033 in 250916 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is higher than 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. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (pathogenic n=1, VUS n=1, benign/likely benign n=9). Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000513903	SCV004158266	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	VPS13B: BP4, BS2
Molecular Genetics, Royal Melbourne Hospital	RCV000547888	SCV004812762	likely benign	Cohen syndrome	2023-05-04	criteria provided, single submitter	clinical testing	European Non-Finnish population allele frequency is 0.5105% (rs111751379, 680/128770 alleles, 3 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as LIKELY BENIGN. Following criteria are met: BS1
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000081914	SCV004847402	likely benign	not specified	2023-12-28	criteria provided, single submitter	clinical testing	The p.Glu2585Lys variant in VPS13B is classified as likely benign because it has been identified in 0.5% (341/68030) of European chromosomes by gnomAD including 4 homozygotes (http://gnomad.broadinstitute.org, v.3.1.2), which is higher than the expected frequency of a disease cuasing variant in this gene. In addition, computational prediction tools predict that this variant does not impact the protein. ACMG/AMP Criteria applied: BS1, BP4.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000513903	SCV001798786	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000513903	SCV001918522	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000513903	SCV001932502	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000547888	SCV002082654	benign	Cohen syndrome	2019-12-20	no assertion criteria provided	clinical testing