Submissions for variant NM_152564.5(VPS13B):c.8903A>G (p.Asn2968Ser)

gnomAD frequency: 0.00396  dbSNP: rs28940272

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000081920	SCV000113855	benign	not specified	2015-03-25	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000081920	SCV000249424	likely benign	not specified	2017-07-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000513475	SCV000512680	likely benign	not provided	2020-09-21	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26764160, 31943017, 15141358, 31736247)
CeGaT Center for Human Genetics Tuebingen	RCV000513475	SCV000609318	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	VPS13B: BP4
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000513475	SCV000610298	likely benign	not provided	2017-02-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000002955	SCV000630893	likely benign	Cohen syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002313703	SCV000847431	likely benign	Inborn genetic diseases	2023-05-02	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.
Mendelics	RCV000002955	SCV001137686	likely benign	Cohen syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000002955	SCV001322372	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000081920	SCV002074215	likely benign	not specified	2022-01-11	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.8978A>G (p.Asn2993Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0032 in 251260 control chromosomes, predominantly at a frequency of 0.0049 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.96 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. c.8978A>G has been reported in the literature in individuals affected with Cohen Syndrome, including a sibling pair who were homozygous for the variant (Kolehmainen_2004), as well as patients with retinal dystrophies including one case with an alternative explanation for disease (Tiwari_2016, Zenteno_2019). These reports do not provide unequivocal conclusions about association of the variant with Cohen Syndrome. At least one publication reports experimental, yeast-based evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Dziurdzik_2020). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Nine submitters classified the variant as likely benign/benign while one classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign.
New York Genome Center	RCV000002955	SCV002764427	uncertain significance	Cohen syndrome	2021-10-29	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000002955	SCV003920624	likely benign	Cohen syndrome	2022-08-23	criteria provided, single submitter	clinical testing	This variant has been reported in the homozygous state in one individual with Cohen syndrome, segregating with disease in 1 affected family member (Kolehmainen 2004 PMID:15141358). This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.6% [379/68018], and in 4 homozygotes; https://gnomad.broadinstitute.org/variant/8-99820031-A-G?dataset=gnomad_r3), and in ClinVar, with several laboratories classifying it as benign or likely benign (Variation ID:2821). In an vitro binding assay suggests that this variant may slightly reduce the protein's binding ability (Dziurdzik 2020 PMID:31943017); however, these studies may not accurately represent in vivo biological function. 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.
OMIM	RCV000002955	SCV000023113	pathogenic	Cohen syndrome	2004-07-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000002955	SCV001461446	benign	Cohen syndrome	2019-12-29	no assertion criteria provided	clinical testing