3-10149820-T-C

Variant names:

• chr3-10149820-T-C
• rs397516445
• NM_000551.4:c.497T>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000551.4(VHL):​c.497T>C​(p.Val166Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V166I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.26
• Publications: 16 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: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 31 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 19 uncertain in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-10149819-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 3-10149820-T-C is Pathogenic according to our data. Variant chr3-10149820-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 43605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	NM_000551.4	MANE Select	c.497T>C	p.Val166Ala	missense	Exon 3 of 3	NP_000542.1
	VHL	NM_198156.3		c.374T>C	p.Val125Ala	missense	Exon 2 of 2	NP_937799.1
	VHL	NR_176335.1		n.826T>C		non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	ENST00000256474.3	TSL:1 MANE Select	c.497T>C	p.Val166Ala	missense	Exon 3 of 3	ENSP00000256474.3
	VHL	ENST00000345392.3	TSL:1	c.374T>C	p.Val125Ala	missense	Exon 2 of 2	ENSP00000344757.2
	VHL	ENST00000477538.2	TSL:1	n.1377T>C		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000430 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:2

Sep 11, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Val166Ala variant has previously been reported to have occurred de novo in a n individual with clinical features of Von Hippel-Lindau syndrome and has been i dentified in one affected individual previously tested by our laboratory (Hes 20 07, LMM unpublished data). Valine (Val) at position 166 is not evolutionarily co nserved in mammals (rabbit and pika have an isoleucine at this position), howeve r, a different amino acid change at this location (Val166Phe) has also been asso ciated with the clinical features of Von Hippel-Lindau syndrome (Maher 1996). Co mputational analyses (biochemical amino acid properties, conservation, AlignGVGD , PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein, but structural evidence suggests this amino acid plays an importan t role in VHL function (Stebbins 1999). In summary, this variant is highly likel y to be pathogenic based on its de novo occurrence in a patient with sporadic di sease.

Aug 01, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 07, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V166A variant (also known as c.497T>C), located in coding exon 3 of the VHL gene, results from a T to C substitution at nucleotide position 497. The valine at codon 166 is replaced by alanine, an amino acid with similar properties. This alteration was detected in an individual diagnosed with bilateral pheochromocytomas at age 11 (Hes FJ et al. Clin. Genet., 2007 Aug;72:122-9). Another mutation at the same position, p.V166F, has been described in multiple individuals with a clinical diagnosis of Von Hippel-Lindau syndrome (Cruz JB et al, Arq Bras Endocrinol Metabol 2007 Dec; 51(9):1463-7; Gross DJ et al. J. Clin. Endocrinol. Metab. 1996 Jan; 81(1):147-9; Nordstrom-O'Brien M et al. Hum. Mutat. 2010 May;31(5):521-37; Maher ER et al. J. Med. Genet. 1996 Apr; 33(4):328-32). The p.V166A alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. In addition, this alteration is predicted to disrupt enlogin C interaction of pVHL (Forman JR et al. Proteins, 2009 Oct;77:84-96). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	L
PhyloP100		6.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.93	P
Vest4		0.79
MutPred		0.95		Loss of helix (P = 0.0626)
MVP		1.0
MPC		0.91
ClinPred		0.95	D
GERP RS		4.9
Varity_R		0.90
gMVP		0.86
Mutation Taster		=6/94	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: rs397516445; hg19: chr3-10191504;