3-10142092-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000551.4(VHL):​c.245G>C​(p.Arg82Pro) 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 (★★).

Frequency

Genomes: not found (cov: 33)

Consequence

VHL
NM_000551.4 missense

Scores

13
5
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.04
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987
PP5
Variant 3-10142092-G-C is Pathogenic according to our data. Variant chr3-10142092-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 193118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10142092-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VHLNM_000551.4 linkc.245G>C p.Arg82Pro missense_variant Exon 1 of 3 ENST00000256474.3 NP_000542.1 P40337-1A0A024R2F2
VHLNM_001354723.2 linkc.245G>C p.Arg82Pro missense_variant Exon 1 of 3 NP_001341652.1
VHLNM_198156.3 linkc.245G>C p.Arg82Pro missense_variant Exon 1 of 2 NP_937799.1 P40337-2A0A0S2Z4K1
VHLNR_176335.1 linkn.315G>C non_coding_transcript_exon_variant Exon 1 of 4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VHLENST00000256474.3 linkc.245G>C p.Arg82Pro missense_variant Exon 1 of 3 1 NM_000551.4 ENSP00000256474.3 P40337-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:2
Feb 14, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: The variant, VHL c.245G>C (p.Arg82Pro) results in a non-conservative amino acid change located in the von Hippel-Lindau disease tumor suppressor, beta/alpha domain and von Hippel-Lindau disease tumor suppressor, beta domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 227066 control chromosomes (gnomAD) and has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome (Dollfus_2002, Gallou_2004, Chacon-Camacho_2010, Peng_2017). These data indicate that the variant is very likely to be associated with disease. Publications that report experimental evidence evaluating an impact on protein function (Li_2002, German_2016), do not allow convincing conclusions about the variant effect. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

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:1
Dec 02, 2014
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.52
D
BayesDel_noAF
Pathogenic
0.51
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.99
D;.
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.93
D;D
M_CAP
Pathogenic
1.0
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Uncertain
2.5
M;M
PrimateAI
Pathogenic
0.94
D
PROVEAN
Pathogenic
-5.6
D;D
REVEL
Pathogenic
0.95
Sift
Uncertain
0.010
.;D
Sift4G
Uncertain
0.0060
D;D
Polyphen
1.0
D;D
Vest4
0.87
MutPred
0.90
Loss of MoRF binding (P = 0.0065);Loss of MoRF binding (P = 0.0065);
MVP
1.0
MPC
1.3
ClinPred
1.0
D
GERP RS
5.4
Varity_R
0.99
gMVP
0.99

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs794726890; hg19: chr3-10183776; COSMIC: COSV56546439; COSMIC: COSV56546439; API