Submissions for variant NM_152564.5(VPS13B):c.3386A>G (p.Lys1129Arg)

gnomAD frequency: 0.00451  dbSNP: rs61759485

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000081892	SCV000113827	benign	not specified	2013-04-30	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000081892	SCV000249406	likely benign	not specified	2016-11-22	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000081892	SCV000297278	likely benign	not specified	2015-11-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000512666	SCV000512677	benign	not provided	2019-07-17	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19006247, 27353947, 28559085)
CeGaT Center for Human Genetics Tuebingen	RCV000512666	SCV000609316	likely benign	not provided	2022-02-01	criteria provided, single submitter	clinical testing
Invitae	RCV001079908	SCV000630870	benign	Cohen syndrome	2022-11-04	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000512666	SCV000841635	likely benign	not provided	2018-01-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002313809	SCV000849223	benign	Inborn genetic diseases	2018-11-28	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Illumina Laboratory Services, Illumina	RCV001079908	SCV001322033	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.
Genome-Nilou Lab	RCV001079908	SCV001716386	likely benign	Cohen syndrome	2021-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000081892	SCV002547503	benign	not specified	2022-05-10	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.3386A>G (p.Lys1129Arg) results in a 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 0.0046 in 251224 control chromosomes in the gnomAD database, including 5 homozygotes. The observed variant frequency is approximately 1.9 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.3386A>G 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.
Fulgent Genetics, Fulgent Genetics	RCV001079908	SCV002798769	benign	Cohen syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001079908	SCV003920623	likely benign	Cohen syndrome	2022-07-15	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in at least 3 individuals with retinal disease including 1 individual with Cohen syndrome (Seifert 2009 PMID:19006247, Tiwari 2016 PMID:27353947, Stone 2017 PMID:28559085). Of note, at least 1 publication notes that this variant is not likely to be disease causing. This variant is present in the Genome Aggregation Database (Highest reported MAF 0.6% (417/68028) including 1 homozygote (https://gnomad.broadinstitute.org/variant/8-99442576-A-G?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as Benign or Likely Benign (Variation ID:95845). Evolutionary conservation for this variant is unclear; suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign.
Natera, Inc.	RCV001079908	SCV001456263	benign	Cohen syndrome	2020-01-06	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000512666	SCV001917361	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000081892	SCV001953776	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000512666	SCV001975186	likely benign	not provided		no assertion criteria provided	clinical testing