rs869025636

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000551.4(VHL):​c.340G>A​(p.Gly114Ser) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G114C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

VHL
NM_000551.4 missense, splice_region

Scores

10
4
3
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 4.53
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 18 ACMG points.

PM1
In a region_of_interest Involved in binding to CCT complex (size 55) in uniprot entity VHL_HUMAN there are 32 pathogenic changes around while only 1 benign (97%) 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 chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.985
PP5
Variant 3-10142187-G-A is Pathogenic according to our data. Variant chr3-10142187-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 583094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
VHLNM_000551.4 linkuse as main transcriptc.340G>A p.Gly114Ser missense_variant, splice_region_variant 1/3 ENST00000256474.3 NP_000542.1 P40337-1A0A024R2F2
VHLNM_001354723.2 linkuse as main transcriptc.340G>A p.Val114Ile missense_variant, splice_region_variant 1/3 NP_001341652.1
VHLNM_198156.3 linkuse as main transcriptc.340G>A p.Val114Met missense_variant, splice_region_variant 1/2 NP_937799.1 P40337-2A0A0S2Z4K1
VHLNR_176335.1 linkuse as main transcriptn.410G>A splice_region_variant, non_coding_transcript_exon_variant 1/4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
VHLENST00000256474.3 linkuse as main transcriptc.340G>A p.Gly114Ser missense_variant, splice_region_variant 1/31 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:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 24, 2020This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that while this missense change does not affect microtubule stabilization, it does exhibit disrupted microtubule turnover, reduced assembly of the VCB-Cul2 complex, and decreased HIF-1 alpha binding and ubiquitination (PMID: 11865071, 12510195, 20855504). Other missense substitutions at this codon (p.Gly114Arg and p.Gly114Cys) have been reported in individuals affected with VHL syndrome (PMID: 7728151, 27527340, 7987306). This suggests that the glycine residue is critical for VHL protein function and that other missense substitutions at this position may also be pathogenic. This variant has been reported in individuals and families affected with von Hippel-Lindau (VHL) syndrome, or VHL-associated lesions (PMID: 20660572, 23407287, 15002726, Invitae). This variant is also known as c.553G>A in the literature. This sequence change replaces glycine with serine at codon 114 of the VHL protein (p.Gly114Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant also falls at the last nucleotide of exon 1 of the VHL coding sequence, which is part of the consensus splice site for this exon. -
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsSep 14, 2023The p.G114S pathogenic mutation (also known as c.340G>A), located in coding exon 1 of the VHL gene, results from a G to A substitution at nucleotide position 340. The glycine at codon 114 is replaced by serine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 1 and may have some effect on normal mRNA splicing. In functional studies, this alteration was shown to reduce binding and decrease ability to ubiquinate a critical transcription factor HIF1-alpha (Hansen WJ et al. Mol Cell Biol, 2002 Mar;22:1947-60). In addition, this alteration was shown to moderately decrease microtubule regulatory functions compared to the wildtype VHL protein (Thoma CR et al. J Cell Biol, 2010 Sep;190(6):991-1003). This alteration has been reported in multiple individuals with features of VHL and/or a clinical diagnosis of VHL (Loughrey PB et al. Endocr Relat Cancer, 2022 Oct;29:R157-R172; Petenuci J et al. Clin Endocrinol (Oxf), 2021 Jul;95:117-124; Krauss T et al. Endocr Relat Cancer, 2018 Sep;25:783-793; Erlic Z et al. Endocr Relat Cancer, 2010 Dec;17:875-83). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. This amino acid position is highly conserved in available vertebrate species. In addition, as a missense substitution this is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.65
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.84
D
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.71
T
M_CAP
Pathogenic
0.99
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Pathogenic
1.0
D
PrimateAI
Pathogenic
0.83
D
PROVEAN
Uncertain
-2.4
N
REVEL
Pathogenic
0.81
Sift4G
Benign
0.13
T
Polyphen
1.0
D
Vest4
0.68
MutPred
0.89
Loss of sheet (P = 0.007);
MVP
1.0
MPC
0.89
ClinPred
0.95
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8
Varity_R
0.89
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
1.0
SpliceAI score (max)
0.33
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.22
Position offset: 46
DS_DL_spliceai
0.33
Position offset: 0

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: rs869025636; hg19: chr3-10183871; COSMIC: COSV56546928; COSMIC: COSV56546928; API