3-10142038-G-C

Position:

• chr3-10142038-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS3_Supporting PM1 PM6_Supporting PP3 PS4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000551.3(VHL):c.191G>C (p.Arg64Pro) variant in the VHL gene is absent from gnomAD v4.1.0 (PM2_Supporting). This variant resides within a region, amino acids 63 - 155 (Beta domain), of VHL that is defined as a mutational hotspot and critical functional domain by the ClinGen VHL VCEP (PM1). The computational predictor REVEL gives a score of 0.938, which is above the threshold of 0.664, evidence that correlates with impact to VHL function (PP3). This variant has been reported in 11 probands with features of Von-Hippel-Lindau syndrome/ meeting Danish criteria (9.25 points, PS4; PMID:19336503, 9663592, 17661816, 30455982, 28646318, 31383958, 19576851, 17639058, 28944243, 17102083, 21463266). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in an individual with bilateral pheochromocytoma (PM6_Supporting; PMID:24555745). In vitro assays show conflicting results but suggest this variant impacts protein function as shown by reduced binding and ubiquitination of HIF-alpha (PMID:16452184, 15611064, 11331612) (PS3_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA020089/MONDO:0008667/078

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 6.15

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.191G>C	p.Arg64Pro	missense_variant	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.191G>C	p.Arg64Pro	missense_variant	1/3		NP_001341652.1
VHL	NM_198156.3	c.191G>C	p.Arg64Pro	missense_variant	1/2		NP_937799.1
VHL	NR_176335.1	n.261G>C		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.191G>C	p.Arg64Pro	missense_variant	1/3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen VHL Variant Curation Expert Panel, ClinGen	Jun 25, 2024	The NM_000551.3(VHL):c.191G>C (p.Arg64Pro) variant in the VHL gene is absent from gnomAD v4.1.0 (PM2_Supporting). This variant resides within a region, amino acids 63 - 155 (Beta domain), of VHL that is defined as a mutational hotspot and critical functional domain by the ClinGen VHL VCEP (PM1). The computational predictor REVEL gives a score of 0.938, which is above the threshold of 0.664, evidence that correlates with impact to VHL function (PP3). This variant has been reported in 11 probands with features of Von-Hippel-Lindau syndrome/ meeting Danish criteria (9.25 points, PS4; PMID: 19336503, 9663592, 17661816, 30455982, 28646318, 31383958, 19576851, 17639058, 28944243, 17102083, 21463266). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in an individual with bilateral pheochromocytoma (PM6_Supporting; PMID: 24555745). In vitro assays show conflicting results but suggest this variant impacts protein function as shown by reduced binding and ubiquitination of HIF-alpha (PMID: 16452184, 15611064, 11331612) (PS3_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 01, 2018	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 13, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2024	While some published functional studies support a damaging effect including reduced hypoxia-inducible factor (HIF)-1a binding, inability to degrade HIF2a, impaired EPO receptor (EPOR) binding, and defective fibronectin extracellular matrix (ECM) assembly, others demonstrate retained HIF1a binding, retained ability to degrade HIF2a, normal downregulation of HIFa target genes, and retained VEC complex formation (PMID: 11331612, 12944410, 15611064, 16452184, 17700531, 26846855); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.404G>A, p.(R105P); This variant is associated with the following publications: (PMID: 19408298, 18836774, 29748190, 21463266, 19336503, 9663592, 19808854, 17661816, 19576851, 17639058, 17102083, 20151405, 18043261, 26269449, 30877234, 28944243, 28646318, 11331612, 16452184, 15611064, 17700531, 12944410, 26846855, 24555745, 19955664, 32832168, 32487141) -

Pheochromocytoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 29, 1998

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 05, 2024

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 64 of the VHL protein (p.Arg64Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Von Hippel-Lindau (VHL) syndrome and pheochromocytoma (PMID: 9663592, 17102083, 17661816, 19336503, 24555745). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2226). 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, 15611064, 16452184). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 26, 2024

The p.R64P pathogenic mutation (also known as c.191G>C), located in coding exon 1 of the VHL gene, results from a G to C substitution at nucleotide position 191. The arginine at codon 64 is replaced by proline, an amino acid with dissimilar properties. This mutation has been reported in multiple individuals and/or families diagnosed with VHL (van der Harst E et al. Int J Cancer. 1998 Jul 29;77(3):337-40; Hoffman MA et al. Hum. Mol. Genet. 2001 May;10:1019-27; Hes FJ et al. Clin Genet. 2007 Aug;72(2):122-9; Boedeker CC et al. J. Clin. Endocrinol. Metab. 2009 Jun;94:1938-44; Wittström E et al. Ophthalmic Genet. 2014 Jun;35:91-106). In addition, a 23-year-old female diagnosed with a neck PGL who had a family history of PCCs and clear cell renal cell carcinoma was found to carry this alteration, and her tumor showed LOH for the wild-type allele (Gaal J et al. J Clin Endocrinol Metab. 2009 Nov;94(11):4367-71). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0060	.;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;D
Vest4		0.89
MutPred		0.83		Loss of MoRF binding (P = 8e-04);Loss of MoRF binding (P = 8e-04);
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs104893826; hg19: chr3-10183722; COSMIC: COSV56553894; COSMIC: COSV56553894;