ClinVar Miner

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

gnomAD frequency: 0.00068  dbSNP: rs145208175
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Total submissions: 13
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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
Labcorp Genetics (formerly Invitae), Labcorp 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 2024-02-21 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 (PMID: 30792901); 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: 28569743, 30792901)
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.
Clinical Genetics Laboratory, Skane University Hospital Lund RCV000724114 SCV005198990 uncertain significance not provided 2023-06-18 criteria provided, single submitter clinical testing
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

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