rs5030821

Variant names:

• chr3-10149823-G-A
• rs5030821
• NM_000551.4:c.500G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-10149823-G-A
• chr3-10149823-G-C
• chr3-10149823-G-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM6 PM1 PS3_Supporting PP3 PM2_Supporting PS4

This summary comes from the ClinGen Evidence Repository: The NM_000551.4(VHL):c.500G>A (p.Arg167Gln) variant in VHL is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 167. This missense mutation has been identified in at least 19 unrelated individuals with von Hippel-Lindau disease. Mostly VHL Type 2 or 2B phenotypes are noted. However, some publications describe VHL Type 1 as well. PMIDs used: 20846682, 8707293, 9829912, 9829911, 7728151, 12114495, 12624160, 14722919. CIViC EIDs used (https://civicdb.org): 5485, 5354, 5264, 5062, 4913, 5487, 5546, 6118. 2 participating commercial laboratories reported >7 and >20 cases. The number of proband and/or family cases fulfills the criteria for strong evidence (PS4). Multiple publications (PMID:15574766, PMID:19030229) support disruption of Elongin C binding with the Arg167Gln variant, as well as altered regulation of HIF2a and near wild type regulation via ubiquitination of HIF1a (PS3_Supporting). A de novo (and mosaic ~5.5% allele freq in blood and ~34% in a pheochromocytoma at ~80% tumor purity) case was identified in a 16yo with no family history of VHL and fulfilling Danish Criteria for VHL (The 16yo had the following: Hb, pheochromocytoma, pancreatic endocrine tumor, left adrenal nodule). PMID:30731206, CIViC evidence ID: EID7714. 1 commercial laboratory reports a de novo case in a child with bilateral retinal hemangiomas in the age range of 10yo (PM6). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Arg167 is one of the germline hotspots outlined by the VHL VCEP, and it is in the Elongin binding domain (PM1). The computational predictor REVEL gives a score of 0.874, which is above the threshold of >=0.664, evidence that correlates with impact to VHL function (PP3). Per VHL VCEP specifications, this code is applied when the REVEL score is >=0.6. (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel-Lindau disease (VHL disease) 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/CA020454/MONDO:0008667/078

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:19 U:1
• Conservation: PhyloP100: 7.78
• Publications: 105 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp, G2P
• 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

Specifications for VHL are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000551.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	NM_000551.4	MANE Select	c.500G>A	p.Arg167Gln	missense	Exon 3 of 3	NP_000542.1	A0A024R2F2
	VHL	NM_198156.3		c.377G>A	p.Arg126Gln	missense	Exon 2 of 2	NP_937799.1	A0A0S2Z4K1
	VHL	NM_001354723.2		c.*54G>A		3_prime_UTR	Exon 3 of 3	NP_001341652.1	A0A8Q3WL21

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	ENST00000256474.3	TSL:1 MANE Select	c.500G>A	p.Arg167Gln	missense	Exon 3 of 3	ENSP00000256474.3	P40337-1
	VHL	ENST00000345392.3	TSL:1	c.377G>A	p.Arg126Gln	missense	Exon 2 of 2	ENSP00000344757.2	P40337-2
	VHL	ENST00000477538.2	TSL:1	n.1380G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251434 AF XY: 0.00

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000495 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
9	-	-	Von Hippel-Lindau syndrome (9)
6	1	-	not provided (7)
1	-	-	Chuvash polycythemia (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Pheochromocytoma (1)
1	-	-	Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.8
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.97		Gain of ubiquitination at K171 (P = 0.0397)
MVP		1.0
MPC		1.1
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.91
Mutation Taster		=10/90	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: rs5030821; hg19: chr3-10191507; COSMIC: COSV56547786;