Submissions for variant NM_152564.5(VPS13B):c.7712C>T (p.Ser2571Phe)

gnomAD frequency: 0.00068  dbSNP: rs145208175

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724114	SCV000230597	uncertain significance	not provided	2017-01-11	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000194337	SCV000249421	uncertain significance	not specified	2014-04-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000283654	SCV000470826	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Fulgent Genetics, Fulgent Genetics	RCV000283654	SCV000611532	uncertain significance	Cohen syndrome	2017-05-23	criteria provided, single submitter	clinical testing
Invitae	RCV000283654	SCV000630888	likely benign	Cohen syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002317049	SCV000850399	likely benign	Inborn genetic diseases	2021-05-28	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.
GeneDx	RCV000724114	SCV001823763	uncertain significance	not provided	2022-09-08	criteria provided, single submitter	clinical testing	Observed with a variant on the same allele (in cis) and another variant on the opposite allele (in trans) in a patient with developmental delay, microcephaly, and dysmorphic features in the published literature (Scocchia et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30792901, 28569743)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000194337	SCV002547499	uncertain significance	not specified	2022-05-10	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.7787C>T (p.Ser2596Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00074 in 250642 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in VPS13B causing Cohen Syndrome (0.00074 vs 0.0025), allowing no conclusion about variant significance. c.7787C>T has been reported in the literature as a non-informative genotype in at-least one individual with a presumed diagnosis of Cohen syndrome who underwent a trio based whole genome sequencing (WGS) analysis (example, Scocchia_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Cohen Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven 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 (VUS, n=5; Likely Benign, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Athena Diagnostics	RCV000724114	SCV004229553	uncertain significance	not provided	2023-08-25	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools predict that this variant is not damaging.
Natera, Inc.	RCV000283654	SCV001461437	likely benign	Cohen syndrome	2020-06-04	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000724114	SCV001925012	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000724114	SCV001968667	uncertain significance	not provided		no assertion criteria provided	clinical testing