rs786202857

Positions:

• chr3-10142056-A-C
• chr3-10142056-A-G
• chr3-10142056-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000551.4(VHL):​c.209A>C​(p.Glu70Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E70K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.41

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain von Hippel-Lindau disease tumor suppressor (size 212) in uniprot entity VHL_HUMAN there are 96 pathogenic changes around while only 8 benign (92%) 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 chr3-10142055-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.209A>C	p.Glu70Ala	missense_variant	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.209A>C	p.Glu70Ala	missense_variant	1/3		NP_001341652.1
VHL	NM_198156.3	c.209A>C	p.Glu70Ala	missense_variant	1/2		NP_937799.1
VHL	NR_176335.1	n.279A>C		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.209A>C	p.Glu70Ala	missense_variant	1/3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 23, 2021

This variant disrupts the p.Glu70 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9829912, 17661816, 19270817, 19408298, 25078357, 25562111, 25715769, 27439424). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals affected with VHL-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 70 of the VHL protein (p.Glu70Ala). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.79	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	1.7	L;L
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.4	N;D
REVEL	Uncertain	0.48
Sift	Benign	0.092	.;T
Sift4G	Benign	0.33	T;T
Polyphen		0.0030	B;B
Vest4		0.29
MutPred		0.67		Gain of glycosylation at S72 (P = 0.0212);Gain of glycosylation at S72 (P = 0.0212);
MVP		1.0
MPC		0.73
ClinPred		0.84	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-10183740;