3-10142080-A-G

Position:

• chr3-10142080-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS3_Supporting PM1 PP3 PM6 PS4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The variant NM_000551.4(VHL):c.233A>G (p.Asn78Ser) is a missense variant predicted to cause substitution of Asparagine by Serine. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This is identified in over 16 probands meeting either Danish criteria for VHL, or harboring other consistent features with VHL. The total phenotype points is 15.25, which meets the VHL VCEP specification of PS4 (5-15 phenotype points) (PMIDs:728151; 23842656; 25952756; 21463266; 25078357; 8634692; 23407287; 8707293; 8730290; 18067796; 12114495; 12202531; 17024664; 28388566; 18446368; 10567493; 29294023; 11850829) This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with VHL (PMID:12114495) (PM6). This variant is also seen 4 times in cancerhotspots.org, which meets the criteria of PM1_Supporting, when using somatic data to inform a germline variant curation. However, as the variant resides in the first Beta domain of VHL, a critical functional domain, it meets the full moderate criteria of (PM1). Functional data shows this variant did not alter expression of HIF1a (102% for HIF1α , similar to the truncating control used) and 86% expression for HIF2α (PS3_Supporting; PMID:21715564). The computational predictor REVEL gives a score of 0.767, 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 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/CA020131/MONDO:0008667/078

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 5.72

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 11 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.233A>G	p.Asn78Ser	missense_variant	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.233A>G	p.Asn78Ser	missense_variant	1/3		NP_001341652.1
VHL	NM_198156.3	c.233A>G	p.Asn78Ser	missense_variant	1/2		NP_937799.1
VHL	NR_176335.1	n.303A>G		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.233A>G	p.Asn78Ser	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:12

Revision: reviewed by expert panel

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genomics Labs, University Health Network	Jul 10, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 19, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 28, 2020	Variant summary: VHL c.233A>G (p.Asn78Ser) results in a conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, beta domain (IPR024053) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 230680 control chromosomes (gnomAD). c.233A>G has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome and has been shown to co-segregate with disease in different families (e.g. Zbar_1996, Cybulski_2002, Dollfus_2002, Huang_2004). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant impairs protein function and stability and results in compromised tight junction formation, disorganized cell morphology and increased HIF (hypoxia-inducible factor) activation (e.g. Bangiyeva_2009, Bond_2011). Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen VHL Variant Curation Expert Panel, ClinGen	Jun 25, 2024	The variant NM_000551.4(VHL):c.233A>G (p.Asn78Ser) is a missense variant predicted to cause substitution of Asparagine by Serine. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This is identified in over 16 probands meeting either Danish criteria for VHL, or harboring other consistent features with VHL. The total phenotype points is 15.25, which meets the VHL VCEP specification of PS4 (5-15 phenotype points) (PMIDs:728151; 23842656; 25952756; 21463266; 25078357; 8634692; 23407287; 8707293; 8730290; 18067796; 12114495; 12202531; 17024664; 28388566; 18446368; 10567493; 29294023; 11850829) This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with VHL (PMID:12114495) (PM6). This variant is also seen 4 times in cancerhotspots.org, which meets the criteria of PM1_Supporting, when using somatic data to inform a germline variant curation. However, as the variant resides in the first Beta domain of VHL, a critical functional domain, it meets the full moderate criteria of (PM1). Functional data shows this variant did not alter expression of HIF1a (102% for HIF1α , similar to the truncating control used) and 86% expression for HIF2α (PS3_Supporting; PMID:21715564). The computational predictor REVEL gives a score of 0.767, 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 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, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 26, 2016	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 05, 2024	The VHL c.233A>G (p.Asn78Ser) variant has been reported in the published literature in individuals with von Hippel-Lindau (VHL) syndrome (PMID: 15300849 (2004), 19464396 (2009), 23842656 (2013), 27439424 (2016), 28388566 (2017), 32742360 (2020), 33720516 (2021)). This variant has also been identified in individuals with renal cell carcinoma (PMID: 35441217 (2002), 37405915 (2023)) and pheochromocytoma and paraganglioma (PPGL) (PMID: 37529773 (2023)). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 11739384 (2022), 19602254 (2009)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2022	Published functional studies demonstrate a damaging effect: an unstable protein resulting in up-regulation of HIF-2a and Glut-1, down-regulation of P27, and the disruption of pVHL and hVDU1 interactions in vitro (Li et al., 2002; Bangiyeva et al., 2009; Rechsteiner et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 446A>G; This variant is associated with the following publications: (PMID: 8730290, 16775032, 8707293, 19602254, 18836774, 23757202, 8634692, 7553625, 15300849, 17661816, 11409863, 12202531, 7591282, 10567493, 17024664, 14767899, 21362373, 9452106, 21454469, 11739384, 21715564, 10408776, 7728151, 25563310, 23842656, 27530247, 27439424, 26984080, 27527340, 12114495, 15109448, 30338240, 30787465, 8956040, 33720516, 18446368, 20233476, 28559085, 32742360) -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 06, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 03, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Feb 02, 2024	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 03, 2022

This variant is also known as N149S. This missense change has been observed in individual(s) with von Hippel–Lindau disease (PMID: 7728151, 8956040, 12114495, 15109448, 15300849, 19464396, 23842656). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 78 of the VHL protein (p.Asn78Ser). ClinVar contains an entry for this variant (Variation ID: 93326). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects VHL function (PMID: 19602254, 21454469). 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. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 02, 2021

The p.N78S pathogenic mutation (also known as c.233A>G) is located in coding exon 1 of the VHL gene and results from an A to G substitution at nucleotide position 233. The asparagine at codon 78 is replaced by serine, an amino acid with highly similar properties. This mutation has been reported in multiple individuals and families with VHL and has been shown to co-segregate with disease (Chen et al. Hum Mut. 1995; 5(1): 66-75; Zbar et al. Hum Mut. 1996 8:348-357; Cybulski et al. J Med Genet. 2002 Jul;39(7):E38; Zhang et al. J Cancer Res Clin Oncol. 2008 Nov;134(11):1211-8; Siu et al. Chin Med J (Engl). 2011 Jan;124(2):237-41; Lee JS et al. BMC Med. Genet. 2016 07;17(1):48; Cingoz S et al. Fam Cancer 2013 Mar;12(1):111-7; Lin G et al. Exp Ther Med 2020 Aug;20(2):1237-1244; Qi XP et al. Mol Med Rep 2013 Sep;8(3):799-805). In one study, the p.N78S mutation, a type1 VHL protein mutant, was expressed in VHL-negative renal cell carcinoma cell lines. The authors concluded that VHL has both HIF-á dependent and HIF-á independent functions in regulating tight junctions and cell morphology that likely impact the clinical phenotypes seen in VHL disease (Bangiyeva et al. BMC Cancer 2009. Jul 14;9:229). Of note, this alteration is also referred to as 446A>G (Asn149Ser) in published literature. 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	0.88
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-4.1	D;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.019	D;D
Polyphen		0.99	D;D
Vest4		0.91
MutPred		0.97		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP		1.0
MPC		0.95
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.98

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: rs5030804; hg19: chr3-10183764; COSMIC: COSV56543998; COSMIC: COSV56543998;