ClinVar

Description

The VPS13B p.Val3805Leu variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs138565077) and in ClinVar (classified as a VUS by Inviate, Illumina and Praxis fuer Humangenetik Tuebingen). The variant was also identified in control databases in 56 of 282756 chromosomes at a frequency of 0.000198 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 12 of 35404 chromosomes (freq: 0.000339), European (non-Finnish) in 43 of 129138 chromosomes (freq: 0.000333) and African in 1 of 24956 chromosomes (freq: 0.00004); it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), Other, and South Asian populations. The p.Val3805 residue is conserved in mammals but not in 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. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.