3-10149820-T-C

Position:

• chr3-10149820-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 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 (★★).

• 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

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 16 ACMG points.

• PM1: In a region_of_interest Interaction with Elongin BC complex (size 9) in uniprot entity VHL_HUMAN there are 16 pathogenic changes around while only 0 benign (100%) in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage
• 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 [Likely_pathogenic]. Clinvar id is 43605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10149820-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.497T>C	p.Val166Ala	missense_variant	3/3	ENST00000256474.3	NP_000542.1
VHL	NM_198156.3	c.374T>C	p.Val125Ala	missense_variant	2/2		NP_937799.1
VHL	NM_001354723.2	c.*51T>C		3_prime_UTR_variant	3/3		NP_001341652.1
VHL	NR_176335.1	n.826T>C		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.497T>C	p.Val166Ala	missense_variant	3/3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 11, 2012	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. -
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

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2018

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 v4.3

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;T
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	L;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.9	D;N
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0080	.;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.93	P;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

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: rs397516445; hg19: chr3-10191504;