ClinVar Miner

Submissions for variant NM_152564.5(VPS13B):c.5884G>T (p.Val1962Leu)

gnomAD frequency: 0.00012  dbSNP: rs375399419
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000634094 SCV000755372 benign Cohen syndrome 2024-01-30 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001356249 SCV001714883 uncertain significance not provided 2019-10-21 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV001821796 SCV002071434 uncertain significance not specified 2018-06-12 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003905700 SCV004719186 likely benign VPS13B-related disorder 2022-06-13 criteria provided, single submitter clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Natera, Inc. RCV000634094 SCV001460393 likely benign Cohen syndrome 2019-11-11 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001356249 SCV001551364 uncertain significance not provided no assertion criteria provided clinical testing The VPS13B p.Val1987Leu variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs375399419) and in ClinVar (classified as a VUS by Invitae for Cohen syndrome). The variant was also identified in control databases in 34 of 250242 chromosomes at a frequency of 0.000136 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 17 of 10060 chromosomes (freq: 0.00169), Latino in 9 of 34420 chromosomes (freq: 0.000262), Other in 1 of 6094 chromosomes (freq: 0.000164) and European (non-Finnish) in 7 of 113206 chromosomes (freq: 0.000062); it was not observed in the African, East Asian, European (Finnish) and South Asian populations. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Val1987 residue is conserved in mammals but not more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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