NM_000551.4:c.562C>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: 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

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.

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.562C>G	p.Leu188Val	missense	Exon 3 of 3	NP_000542.1	A0A024R2F2
	VHL	NM_198156.3		c.439C>G	p.Leu147Val	missense	Exon 2 of 2	NP_937799.1	A0A0S2Z4K1
	VHL	NM_001354723.2		c.*116C>G		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.562C>G	p.Leu188Val	missense	Exon 3 of 3	ENSP00000256474.3	P40337-1
	VHL	ENST00000345392.3	TSL:1	c.439C>G	p.Leu147Val	missense	Exon 2 of 2	ENSP00000344757.2	P40337-2
	VHL	ENST00000477538.2	TSL:1	n.1442C>G		non_coding_transcript_exon	Exon 3 of 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

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
9	1	-	Von Hippel-Lindau syndrome (10)
4	-	-	not provided (4)
2	-	-	Chuvash polycythemia (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Au-Kline syndrome (1)
1	-	-	Pheochromocytoma (1)
1	-	-	VHL-related disorder (1)
1	-	-	Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.1
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	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;