ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.388G>C (p.Val130Leu) (rs104893830)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000030586 SCV000053262 pathogenic Von Hippel-Lindau syndrome 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
Ambry Genetics RCV000492250 SCV000580968 pathogenic Hereditary cancer-predisposing syndrome 2018-07-21 criteria provided, single submitter clinical testing The p.V130L pathogenic mutation (also known as c.388G>C) is located in exon 2 of the VHL gene. This alteration results from a G to C substitution at nucleotide position 388. The valine at codon 130 is replaced by leucine, an amino acid with highly similar properties. This alteration has been reported in multiple unrelated patients and families meeting diagnostic criteria for von Hippel-Lindau (VHL) syndrome (Zbar B et al. Hum Mutat. 1996;8(4):348-57; Dollfus H et al. Invest. Ophthalmol. Vis. Sci. 2002 Sep;43(9):3067-74; Gallou C et al. Hum. Mutat. 2004 Sep;24(3):215-24; Wang X et al. Urology. 2014 Mar;83(3):675.e1-5; Ambry internal data). It has also been seen in the compound heterozygous state in one individual with polycythemia (Pastore YD et al. Blood. 2003 Feb;101(4):1591-5). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV001071915 SCV001237247 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2020-09-20 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 130 of the VHL protein (p.Val130Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed as heterozygous in individuals with von Hippel-Lindau syndrome (PMID: 9829912, 10570625, 12202531, 24581539), and in trans (on the opposite chromosome) with a pathogenic variant in an individual with erythrocytosis (PMID: 12393546). ClinVar contains an entry for this variant (Variation ID: 2229). This variant has been reported not to substantially affect VHL protein-to-protein interaction with Tat-binding protein-1 (TBP1) (PMID: 14556007). The clinical significance of this finding is uncertain. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Val130 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 12624160, 20518900, 22393103), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000002317 SCV000022475 pathogenic Erythrocytosis, familial, 2 2003-08-01 no assertion criteria provided literature only
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000030586 SCV000264729 pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing

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