ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.562C>G (p.Leu188Val) (rs5030824)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000210199 SCV000664527 likely pathogenic Hereditary cancer-predisposing syndrome 2016-08-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Moderate segregation with disease (at least 3 informative meioses) for rare diseases.,Other strong data supporting pathogenic classification
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000002311 SCV000264772 pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing
GeneDx RCV000480890 SCV000568596 uncertain significance not provided 2018-08-08 criteria provided, single submitter clinical testing This variant is denoted VHL c.562C>G at the cDNA level, p.Leu188Val (L188V) at the protein level, and results in the change of a Leucine to a Valine (CTG>GTG). This variant, also reported as L259V using alternate nomenclature, has been identified in individuals with Von Hippel Lindau (VHL) syndrome, some of whom were affected with isolated pheochromocytomas, termed VHL type 2C (Crossey 1994, Neumann 2002, Neumann 1995, Ritter 1996, Weirich 2002, Erlic 2010). VHL Leu188Val has been reported to segregate with disease in three families; of note, these families shared a haplotype block that also included another VHL variant, Pro81Ser (Neumann 1995, Ritter 1996, Weirich 2002, Erlic 2010). This variant has been co-observed with a second VHL variant in individuals with recessively-inherited congenital polycythemia, which is generally not associated with VHL-related tumors (Pastore 2003, Bento 2005, Lorenzo 2013, Frantzen 2015). VHL Leu188Val has been evaluated by a number of different functional assays. Most reports have found that VHL Leu188Val is similar to wildtype in its ability to interact with Elongin C, to bind, ubiquitinate, and degrade hypoxia-inducible factor (HIF)-1, and to downregulate HIF-1 target genes (Ohh 2000, Clifford 2001, Hoffman 2001, Gunaratnam 2003, Rathmell 2004, Esteban 2006, Kurban 2006, Hacker 2008, Bangiyeva 2009, Knauth 2009, Heir 2016). However, this variant has also been associated with defective fibronectin extracellular matrix assembly, which may occur independent of the HIF-1 pathway (Hoffman 2001, Rathmell 2004, Kurban 2006, Kurban 2008). Additionally, while Bangiyeva et al. (2009) reported that Leu188Val is associated with normal VHL protein stability, Knauth et al. (2009) found that this variant results in a partially unfolded protein with reduced stability and increased susceptibility to trypic degradation. Finally, while Hoffman et al. (2001) found that Leu188Val suppressed renal carcinoma growth in vivo, Kurban et al. (2006) reported that this variant was associated with highly vascularized tumors with increased invasiveness in a mice. VHL Leu188Val was observed at an allele frequency of 0.006% (7/126710 alleles) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the alpha-domain (Yuen 2009). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence and internal observations, it is unclear whether VHL Leu188Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000002311 SCV000840080 pathogenic Von Hippel-Lindau syndrome 2017-05-24 criteria provided, single submitter clinical testing The c.562C>G (p.Leu188Val) variant has been reported in patients with Von Hippel-Lindau syndrome [PMID 12414898, 12000816]. The variant was originally detected in two families diagnosed with mutiple endocrine neoplasia type IIA but without a RET pathogenic variant [PMID 7563486]. This variant was further detected and characterized as a pathogenic variant in patients with VHL type IIC, a disorder characterized with a risk for pheochromocytoma only [PMID 12414898, 12000816]. This variant was detected in 1/271 patients presenting with non syndromic pheochromocytoma [PMID 12000816]. It was also detected and showed to co- segregate with pheochromocytoma in a family with 6 affected individuals [PMID 12414898]. The variant was found in cis configuration with a p.Pro81Ser variant; however the p.Pro81Ser variant is now classified as likely benign and thus not thought to affect the phenotype of these reported patients. This p.Leu188Val was also reported in two siblings with congenital polycythaemia [PMID 23772956]. In vitro assays showed that this variant affects the extra cellular matrix assembly, which correlated with tumor angiogenesis [PMID 16452184]. The amino acid position 188 of the VHL protein is a hot spot for pathogenic variants causing Von Hippel-Lindau syndrome: additional variants affecting the same amino acid at position 188 (p.Leu188Arg, p.Leu188Gln and p.Leu188Pro) have been reported. This variant was observed in two European (Non Finnish) at the heterozygous state in the ExAC database (http://exac.broadinstitute.org/variant/3-10191569-C-G). Leucine at amino acid position 188 of the VHL protein is highly conserved in mammals and while not clinically validated, computer-based algorithms predict this p.Leu188Val change to be deleterious. This variant is thus classified as pathogenic.
Invitae RCV000627743 SCV000262041 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 188 of the VHL protein (p.Leu188Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs5030824, ExAC 0.003%). This variant has been reported to segregate with von Hippel-Lindau syndrome in three families with most affected individuals presenting only with pheochromocytoma, and has been reported in an individual affected with von Hippel-Lindau syndrome with no pheochromocytoma (PMID: 7563486, 8772572, 7987306). Members of two of the families in which this variant segregated with disease presented additionally with C-cell tumors, C-cell hyperplasia, and medullary thyroid carcinoma (PMID: 7563486). This variant has also been reported in individuals affected with polycythemia (PMID: 12844285, 23772956, 15642680). This variant is also known as Leu259Val, Leu229Val, and C775G in the literature. ClinVar contains an entry for this variant (Variation ID: 2225). Experimental studies have shown that while this missense change does not significantly affect the ability of VHL to ubiquitinate and suppress some of its targets, it does result in impaired fibronectin extracellular matrix assembly and a relatively unstable VHL protein and ubiquitin complex (PMID: 11331612, 16452184, 18567581, 23772956). In addition, renal carcinoma cells containing this variant were shown to be invasive and were capable of inducing vascularized renal cell tumors in a nude mouse xenograft assay (PMID: 19228690). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000002311 SCV000731611 pathogenic Von Hippel-Lindau syndrome 2017-09-01 criteria provided, single submitter clinical testing The p.Leu188Val variant in VHL (also described as p.Leu259Val in the literature) has been reported in the heterozygous state in 6 individuals with von Hippel-Li ndau syndrome type 2C and segregated with disease in at least 12 affected relati ves from 2 families (Neumann 1995, Ritter 1996, Zbar 1996, Neumann 2002, Weirich 2002). This variant has also been reported in the compound heterozygous state i n 3 individuals with congenital polycythemia (Pastore 2003, Bento 2005). Other c linical laboratories have reported this variant in ClinVar (Variation ID 2225). In vitro functional studies provide some evidence that the p.Leu188Val variant m ay impact protein function (Hoffman 2001, Kurban 2006, Knauth 2009). The p.Leu18 8Val variant has also been identified in 7/126710 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conserva tion analysis suggest that the p.Leu188Val variant may impact the protein. In su mmary, this variant meets criteria to be classified as pathogenic for von Hippel -Lindau syndrome type 2C in an autosomal dominant manner based upon case observa tions, segregation studies, and functional and computational evidence. ACMG/AMP codes applied: PS4, PP1_Strong, PS3_Supporting, PP3.
OMIM RCV000002311 SCV000022469 pathogenic Von Hippel-Lindau syndrome 2003-02-15 no assertion criteria provided literature only
OMIM RCV000002312 SCV000022470 pathogenic Erythrocytosis, familial, 2 2003-02-15 no assertion criteria provided literature only
OMIM RCV000002313 SCV000022471 pathogenic Pheochromocytoma 2003-02-15 no assertion criteria provided literature only
University of Washington Department of Laboratory Medicine,University of Washington RCV000210199 SCV000266137 pathogenic Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing

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