rs5030827

Positions:

• chr3-10142097-G-A
• chr3-10142097-G-C
• chr3-10142097-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000551.4(VHL):​c.250G>A​(p.Val84Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V84A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 6.11

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 11 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 12 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 chr3-10142097-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 3-10142097-G-A is Pathogenic according to our data. Variant chr3-10142097-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 428813.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.250G>A	p.Val84Met	missense_variant	1/3	ENST00000256474.3
VHL	NM_001354723.2	c.250G>A	p.Val84Met	missense_variant	1/3
VHL	NM_198156.3	c.250G>A	p.Val84Met	missense_variant	1/2
VHL	NR_176335.1	n.320G>A		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.250G>A	p.Val84Met	missense_variant	1/3	1	NM_000551.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000438 AC: 1 AN: 228506 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 126898

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000967

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451712 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 722542

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 01, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Oct 20, 2021	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 17, 2023

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 84 of the VHL protein (p.Val84Met). This variant is present in population databases (no rsID available, gnomAD 0.001%). This missense change has been observed in individuals with clinical features of von Hippel-Lindau syndrome (PMID: 17688370; external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 428813). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on VHL function (PMID: 17906660). This variant disrupts the p.Val84 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8592333, 11331612, 16502427, 25078357). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2022

The p.V84M variant (also known as c.250G>A), located in coding exon 1 of the VHL gene, results from a G to A substitution at nucleotide position 250. The valine at codon 84 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in an individual affected with bilateral pheochromocytoma diagnosed at ages 1 year and 4 years; of note, this individual's father was also diagnosed with pheochromocytoma at age 40; however, genetic testing was not performed on the father (Stanojevic BR et al. Neoplasma. 2007;54:402-6). It was also identified in a patient diagnosed with a pheochromocytoma at age 8, with recurrence of disease at age 26 (Eisenhofer G et al. Horm. Metab. Res. 2012 May;44(5):343-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	0.98
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	0.82	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-2.0	N;N
REVEL	Pathogenic	0.76
Sift4G	Benign	0.065	T;T
Polyphen		1.0	D;D
Vest4		0.79
MutPred		0.90		Loss of catalytic residue at V84 (P = 0.0857);Loss of catalytic residue at V84 (P = 0.0857);
MVP		1.0
MPC		1.0
ClinPred		0.97	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
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: rs5030827; hg19: chr3-10183781; COSMIC: COSV56557187; COSMIC: COSV56557187;