Submissions for variant NM_000551.4(VHL):c.562C>G (p.Leu188Val)

gnomAD frequency: 0.00004  dbSNP: rs5030824

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000627743	SCV000262041	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 188 of the VHL protein (p.Leu188Val). This variant is present in population databases (rs5030824, gnomAD 0.006%). This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 7563486, 7987306, 8772572, 12844285, 15642680, 23772956). It has also been observed to segregate with disease in related individuals. This variant is also known as Leu259Val, Leu229Val, and C775G. ClinVar contains an entry for this variant (Variation ID: 2225). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects VHL function (PMID: 11331612, 16452184, 18567581, 19228690, 23772956). For these reasons, this variant has been classified as Pathogenic.
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
GeneDx	RCV000480890	SCV000568596	likely pathogenic	not provided	2023-08-16	criteria provided, single submitter	clinical testing	Observed in the heterozygous state in multiple adult individuals without VHL-related tumors tested at GeneDx and in the literature, suggesting this variant may be associated with reduced penetrance (Huang et al., 2018; Panou et al., 2018; eMERGE consortium et al., 2019; Kuhlman et al., 2021; Savatt et al., 2022); Published functional studies demonstrate retained ability to ubiquitinate and degrade hypoxia-inducible factor (HIF)-1 as well as downregulate HIF-1 target genes, normal to reduced protein stability, and retained or reduced protein binding, but also show defective fibronectin extracellular matrix assembly as well as impaired interaction with mitochondrial proteins (Ohh et al., 2000; Clifford et al., 2001; Hoffman et al., 2001; Gunaratnam et al., 2003; Rathmell et al., 2004; Esteban et al., 2006; Kurban et al., 2006; Hacker et al., 2008; Kurban et al., 2008; Bangiyeva et al., 2009; Knauth et al., 2009; Heir et al., 2016; Tedesco et al., 2019; Li et al., 2022); Co-observed with a second VHL variant in individuals with recessively-inherited congenital polycythemia (Pastore et al., 2003; Bento et al., 2005; Lorenzo et al., 2013; Gangat et al., 2022); however, additional evidence is needed to establish whether there is a relationship between this variant and autosomal recessive disease; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as Leu259Val; This variant is associated with the following publications: (PMID: 12097293, 11331613, 23772956, 7987306, 8772572, 11331612, 19030229, 16585181, 8634692, 15177666, 12000816, 19228690, 7563486, 22393103, 11409863, 27517496, 30105105, 30113886, 19602254, 16452184, 18567581, 15642680, 18836774, 19906784, 25371412, 28620007, 27114602, 24969085, 12844285, 28235946, 28945216, 28503092, 8707293, 10878807, 8956040, 29478617, 12944410, 26846855, 15574766, 17898043, 29790589, 29625052, 30890701, 9829911, 31447099, 31980715, 32869749, 34308366, 34720947, 35205407, 34628056, 29748190, 17700531, 35760869, 35668420, 33720516, 35142155, 12414898)
Ambry Genetics	RCV000210199	SCV000664527	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-12-26	criteria provided, single submitter	clinical testing	The p.L188V variant (also known as c.562C>G), located in coding exon 3 of the VHL gene, results from a C to G substitution at nucleotide position 562. The leucine at codon 188 is replaced by valine, an amino acid with highly similar properties. This variant has been reported in several individuals and families with VHL or VHL related tumors (Ritter MM et al. J. Clin. Endocrinol. Metab. 1996 Mar;81(3):1035-7; Neumann HP et al. JAMA. 1995 Oct;274(14):1149-51; Crossey PA et al. Hum. Mol. Genet. 1994 Aug;3(8):1303-8; Weirich G et al. J Clin Endocrinol Metab, 2002 Nov;87:5241-6) and in conjunction with a VHL mutation in multiple individuals affected with autosomal recessive polycythemia (Bento MC et al. Haematologica. 2005 Jan;90(1):128-9; Lorenzo FR et al. Br. J. Haematol. 2013 Sep;162(6):851-3; Pastore Y et al. Am J Hum Genet, 2003 Aug;73:412-9). Functional studies demonstrate that this variant is characteristic of VHL type 2C alterations in that it maintains the ability to ubiquitinate and downregulate key targets such as HIF2a (Hoffman MA et al. Hum. Mol. Genet., 2001 May;10:1019-27; Hacker KE et al. PLoS ONE, 2008 Nov;3:e3801), and is deficient at extracellular matrix formation (Kurban G et al. Cancer Res., 2006 Feb;66:1313-9). Further studies which injected human RCC cells containing this variant into nude mice showed the formation of highly vascularized, invasive tumors in contrast to those containing wild type VHL that formed no tumors (Kurban G et al. Cancer Res., 2006 Feb;66:1313-9). This alteration has been identified in numerous individuals that do not have a diagnosis of VHL, or any VHL associated tumors (Ambry internal data) suggesting this variant may be associated with significantly reduced penetrance. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, p.L188V is likely to be a low penetrance pathogenic variant and may not be associated with classic von Hippel Lindau disease or associated tumors. Clinical correlation is advised.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000002311	SCV000731611	likely pathogenic	Von Hippel-Lindau syndrome	2024-02-07	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-Lindau syndrome type 2C and segregated with disease in at least 12 affected relatives from 2 families (Neumann 1995 PMID: 7563486, Ritter 1996 PMID: 8772572, Zbar 1996 PMID: 8956040, Neumann 2002 PMID: 12000816, Weirich 2002 PMID: 12414898). This variant has also been reported in the compound heterozygous state in 3 individuals with congenital polycythemia (Pastore 2003 PMID: 12844285, Bento 2005 PMID: 15642680). However, it has also been identified in 0.003% (39/1180038) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v4.0.0). Furthermore, it has been identified in multiple adults with no known VHL-related tumors, suggesting that it may be associated with reduced penetrance (Savatt 2022 PMID: 35668420, Ambry Genetics personal communication). This variant has been reported in ClinVar (Variation ID 2225). In vitro functional studies provide some evidence that the p.Leu188Val variant may impact protein function (Hoffman 2001 PMID: 11331612, Kurban 2006 PMID: 16452184, Knauth 2009 PMID: 19228690). Computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant von Hippel-Lindau syndrome type 2C, however its penetrance may be reduced. ACMG/AMP codes applied: PS4_Moderate, PP1_Strong, PS3_Supporting, PP3.
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.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center	RCV000002311	SCV001478193	pathogenic	Von Hippel-Lindau syndrome	2020-12-15	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000002311	SCV001572439	pathogenic	Von Hippel-Lindau syndrome	2021-04-01	criteria provided, single submitter	clinical testing	Variant summary: VHL c.562C>G (p.Leu188Val) results in a conservative amino acid change located in the alpha domain (IPR024048) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251424 control chromosomes (gnomAD). c.562C>G has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome (example: Neumann_1995, Glavac_1996). Individuals from two of these families also had C-cell tumor and extra adrenal pheochromocytoma. The variant also reported to segregate in a family where most of the affected individuals had only pheochromocytoma (Ritter_1996). In functional studies, the variant was able to direct polyubiquitination of transcription factor HIF (hypoxia-inducible factor) but was partially defective to promoting extracellular fibronectin matrix formation (Hoffman_2001). Kurban et al report that in matrigel assays, the renal carcinoma cells expressing the variant were shown to be highly invasive and in nude mouse xenograft assays they were capable of generating highly vascularized tumors (Kurban_2006). These data indicate that the variant is very likely to be associated with disease. Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic (n=6) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000480890	SCV002020861	pathogenic	not provided	2019-04-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000480890	SCV002563751	pathogenic	not provided	2022-04-01	criteria provided, single submitter	clinical testing	VHL: PP1:Strong, PS4, PM1, PS3:Supporting
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV003330076	SCV004037185	likely pathogenic	Au-Kline syndrome		criteria provided, single submitter	not provided
Baylor Genetics	RCV000002312	SCV004208786	pathogenic	Chuvash polycythemia	2023-11-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000002311	SCV004822001	pathogenic	Von Hippel-Lindau syndrome	2024-01-22	criteria provided, single submitter	clinical testing	The c.562C>G (p.Leu188Val) variant in the VHL gene 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.
Myriad Genetics, Inc.	RCV000002311	SCV004933645	likely pathogenic	Von Hippel-Lindau syndrome	2024-02-22	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 7563486, 8772572, 19906784, 34628056].
OMIM	RCV000002311	SCV000022469	pathogenic	Von Hippel-Lindau syndrome	2003-02-15	no assertion criteria provided	literature only
OMIM	RCV000002312	SCV000022470	pathogenic	Chuvash polycythemia	2003-02-15	no assertion criteria provided	literature only
OMIM	RCV000002313	SCV000022471	pathogenic	Pheochromocytoma	2003-02-15	no assertion criteria provided	literature only
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000002311	SCV000264772	pathogenic	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing