3-10149807-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000551.4(VHL):c.484T>C(p.Cys162Arg) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C162F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.39

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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 chr3-10149808-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 43604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 3-10149807-T-C is Pathogenic according to our data. Variant chr3-10149807-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 496067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.484T>C	p.Cys162Arg	missense_variant	3/3	ENST00000256474.3
VHL	NM_198156.3	c.361T>C	p.Cys121Arg	missense_variant	2/2
VHL	NM_001354723.2	c.*38T>C		3_prime_UTR_variant	3/3
VHL	NR_176335.1	n.813T>C		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.484T>C	p.Cys162Arg	missense_variant	3/3	1	NM_000551.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 31, 2016	Variant summary: The c.484C>T (p.Cys162Arg) in VHL gene is a missense change that involves a non-conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant of interest is located within the elongin binding domain, and mutations in this region have been found in multiple VHL patients. The variant is absent from the control population dataset of ExAC but has been reported in multiple affected individuals from VHL families and was proven to segregate with the disease. In addition, codon Cy162 appears to be a hotspot, since other alterations of this codon, p.C162W, p.C162Y and p.C162F, were found in multiple VHL pts. Taking together, the variant was classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 01, 2018	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 26, 2020

For these reasons, this variant has been classified as Pathogenic. A different missense substitution at this codon (p.Cys162Trp) has been determined to be pathogenic (PMID: 17350623, 19270817, 9829912, 25867206, Invitae). This suggests that the cysteine residue is critical for VHL protein function and that other missense substitutions at this position may also be pathogenic. This variant is not present in population databases (ExAC no frequency). Experimental studies have shown that this missense change impairs Elongin C binding and results in reduced apoptosis when compared to wild-type VHL protein (PMID: 28052007). This variant has been reported in individuals and families affected with von Hippel-Lindau syndrome (PMID: 7728151, 8634692, 8641976, 9681856, 8956040). This variant is also known as c.697T>C (p.Cys233Arg) in the literature. ClinVar contains an entry for this variant (Variation ID: 496067). This sequence change replaces cysteine with arginine at codon 162 of the VHL protein (p.Cys162Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.82	T;T
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-8.8	D;D
REVEL	Pathogenic	0.94
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.94		Loss of helix (P = 0.0041);.;
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
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: rs1553620313; hg19: chr3-10191491; COSMIC: COSV56542418;