3-10149885-C-G

Variant names:

• chr3-10149885-C-G
• rs5030824
• NM_000551.4:c.562C>G

Variant summary

Our verdict is Uncertain significance. The variant received -4 ACMG points: 4P and 8B. BS1 PM1 PS3_Supporting PP3 BS2

This summary comes from the ClinGen Evidence Repository: The variant NM_000551.4(VHL):c.562C>G (p.Leu188Val) is a missense variant predicted to cause substitution of Valine for Leucine at position 188. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.00002474 (39/1180038 from European, Non-Finnish Population). This is higher than the ClinGen VHL VCEP threshold of >=0.0000156 (0.00156%) threshold expected for VHL disease (BS1). From pooled laboratory data: 105 probands carried this variant, and none met Danish criteria for VHL. 18/105 had a single VHL feature. 27 known carriers were 60+ years old and did not have VHL phenotypes. At least 11 of those 60+ without VHL features had no VHL features reported in the family history (BS2), while 8 had VHL features reported in family history (including a carrier relative who met diagnostic VHL criteria). In most functional studies reviewed, results for this variant were consistent with aberrant extra cellular matrix formation / fibronectin assembly (PMIDs: 19602254, 16452184, 17700531, 15574766, 16585181, 11331612, 18567581). However, for HIF1/2 alpha interaction/regulation and VCB complex formation/stability, most studies showed intact function with some slight effects on complex stability. (PMIDs: 30890701 ,15574766, 12944410, 10878807, 16585181, 19030229, 11331612, 11331613, 19228690, 16452184, 23772956, 19602254.) (PS3_Supporting). The L188V variant is located within the alpha domain (156-192), a key functional domain of VHL (PM1). The computational predictor REVEL gives a score of 0.796, which is above the threshold of >=0.664, evidence that correlates with impact to VHL function (PP3). In summary, this variant meets the criteria to be classified as Uncertain for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). Note: This variant has been reported as a putative low penetrance VHL type 2C variant; however at this time, the VHL VCEP does not have low-penetrance specific classification recommendations (see ClinGen Low Penetrance / Risk Allele Working Group). LINK:https://erepo.genome.network/evrepo/ui/classification/CA020488/MONDO:0008667/078

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:21 U:1
• Conservation: PhyloP100: 2.13
• Publications: 67 publications found

Genes affected

VHL (HGNC:12687): (von Hippel-Lindau tumor suppressor) This gene encodes a component of a ubiquitination complex. The encoded protein is involved in the ubiquitination and degradation of hypoxia-inducible-factor (HIF), which is a transcription factor that plays a central role in the regulation of gene expression by oxygen. In addition to oxygen-related gene expression, this protein plays a role in many other cellular processes including cilia formation, cytokine signaling, regulation of senescence, and formation of the extracellular matrix. Variants of this gene are associated with von Hippel-Lindau syndrome, pheochromocytoma, erythrocytosis, renal cell carcinoma, and cerebellar hemangioblastoma. [provided by RefSeq, Jun 2022]

VHL Gene-Disease associations (from GenCC):

• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• von Hippel-Lindau disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal recessive secondary polycythemia not associated with VHL gene

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• Chuvash polycythemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000287086 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received -4 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.562C>G	p.Leu188Val	missense_variant	Exon 3 of 3	ENST00000256474.3	NP_000542.1
VHL	NM_198156.3	c.439C>G	p.Leu147Val	missense_variant	Exon 2 of 2		NP_937799.1
VHL	NR_176335.1	n.891C>G		non_coding_transcript_exon_variant	Exon 4 of 4
VHL	NM_001354723.2	c.*116C>G		3_prime_UTR_variant	Exon 3 of 3		NP_001341652.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.562C>G	p.Leu188Val	missense_variant	Exon 3 of 3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251424 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461884 Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74324

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:21 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:9 Uncertain:1

Feb 26, 2016

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 15, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 25, 2024

ClinGen VHL Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The variant NM_000551.4(VHL):c.562C>G (p.Leu188Val) is a missense variant predicted to cause substitution of Valine for Leucine at position 188. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.00002474 (39/1180038 from European, Non-Finnish Population). This is higher than the ClinGen VHL VCEP threshold of >=0.0000156 (0.00156%) threshold expected for VHL disease (BS1). From pooled laboratory data: 105 probands carried this variant, and none met Danish criteria for VHL. 18/105 had a single VHL feature. 27 known carriers were 60+ years old and did not have VHL phenotypes. At least 11 of those 60+ without VHL features had no VHL features reported in the family history (BS2), while 8 had VHL features reported in family history (including a carrier relative who met diagnostic VHL criteria). In most functional studies reviewed, results for this variant were consistent with aberrant extra cellular matrix formation / fibronectin assembly (PMIDs: 19602254, 16452184, 17700531, 15574766, 16585181, 11331612, 18567581). However, for HIF1/2 alpha interaction/regulation and VCB complex formation/stability, most studies showed intact function with some slight effects on complex stability. (PMIDs: 30890701 ,15574766, 12944410, 10878807, 16585181, 19030229, 11331612, 11331613, 19228690, 16452184, 23772956, 19602254.) (PS3_Supporting). The L188V variant is located within the alpha domain (156-192), a key functional domain of VHL (PM1). The computational predictor REVEL gives a score of 0.796, which is above the threshold of >=0.664, evidence that correlates with impact to VHL function (PP3). In summary, this variant meets the criteria to be classified as Uncertain for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). Note: This variant has been reported as a putative low penetrance VHL type 2C variant; however at this time, the VHL VCEP does not have low-penetrance specific classification recommendations (see ClinGen Low Penetrance / Risk Allele Working Group). -

Feb 07, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Feb 22, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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]. -

Jan 22, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Dec 15, 2020

Department of Pediatrics, Memorial Sloan Kettering Cancer Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 24, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Mar 14, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

not provided Pathogenic:4

Apr 04, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

VHL: PM1, PM2, PM5, PP1:Moderate, PS4:Moderate, PS3:Supporting -

Jun 25, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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 (PMID: 29625052, 30113886, 31447099, 34720947, 35668420); Co-observed with a second VHL variant in individuals with recessively-inherited congenital polycythemia; however, additional evidence is needed to establish whether there is a relationship between this variant and autosomal recessive disease (PMID: 12844285, 15642680, 23772956, 35142155); 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 (PMID: 10878807, 11331613, 11331612, 12944410, 15574766, 16585181, 16452184, 19030229, 17700531, 19602254, 19228690, 26846855, 30890701, 35760869); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); 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, 36451132, 36744932) -

Jul 27, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PP5, PS3 -

Chuvash polycythemia Pathogenic:2

Feb 15, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 20, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jan 08, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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 variant was also determined to be functionally deleterious in one saturation genome editing assay (Buckley M et al. Nat Genet 2024 Jul;56(7):1446-1455). 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. -

Nov 20, 2015

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

VHL-related disorder Pathogenic:1

May 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The VHL c.562C>G variant is predicted to result in the amino acid substitution p.Leu188Val. This variant has been reported in several individuals with Von Hippel-Lindau syndrome or pheochromocytoma, and shown to co-segregate with the disease in multiple families (Neumann et al. 1995. PubMed ID: 7563486; Lorenzo et al. 2013. PubMed ID: 23772956; Neumann et al. 2002. PubMed ID: 12000816; Weirich et al. 2002. PubMed ID: 12414898). It has also been identified in adult individuals with no known VHL-related tumors, suggesting that it may be associated with reduced penetrance (Savatt et al. 2022. PMID: 35668420). Functional studies have produced variable results, but on whole suggest a reduction in protein function (see for example, Hoffman et al. 2001. PubMed ID: 11331612; Knauth et al. 2009. PubMed ID: 19228690; Lorenzo et al. 2013. PubMed ID: 23772956; Bangiyeva et al. 2009. PubMed ID: 19602254). This variant is reported in 0.0039% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is reported from uncertain to pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/2225). This variant is interpreted as likely pathogenic. -

Au-Kline syndrome Pathogenic:1

-

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Pheochromocytoma Pathogenic:1

Feb 15, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Pathogenic:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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 clinical features of autosomal dominant von Hippel-Lindau disease as well as unaffected individuals (PMID: 7563486, 7987306, 8772572, 12000816; external communication, internal data). It has also been observed to segregate with disease in related individuals. This variant has been reported in individual(s) with polycythemia (PMID: 12844285, 15642680, 23772956); however, the role of the variant in this condition is currently unclear. This variant is also known as Leu259Val, Leu229Val, and C775G. ClinVar contains an entry for this variant (Variation ID: 2225). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.48
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M;.
PhyloP100		2.1
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.0	N;N
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.62
MutPred		0.95		Gain of glycosylation at Y185 (P = 0.0103);.;
MVP		1.0
MPC		1.1
ClinPred		0.57	D
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.94
gMVP		0.89
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs5030824; hg19: chr3-10191569;