3-10149878-C-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_000551.4(VHL):​c.555C>G​(p.Tyr185*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

VHL
NM_000551.4 stop_gained

Scores

2
5

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: -0.244
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 14 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-10149878-C-G is Pathogenic according to our data. Variant chr3-10149878-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 223233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VHLNM_000551.4 linkc.555C>G p.Tyr185* stop_gained Exon 3 of 3 ENST00000256474.3 NP_000542.1 P40337-1A0A024R2F2
VHLNM_198156.3 linkc.432C>G p.Tyr144* stop_gained Exon 2 of 2 NP_937799.1 P40337-2A0A0S2Z4K1
VHLNM_001354723.2 linkc.*109C>G 3_prime_UTR_variant Exon 3 of 3 NP_001341652.1
VHLNR_176335.1 linkn.884C>G non_coding_transcript_exon_variant Exon 4 of 4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VHLENST00000256474.3 linkc.555C>G p.Tyr185* stop_gained Exon 3 of 3 1 NM_000551.4 ENSP00000256474.3 P40337-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingGenomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of PhiladelphiaFeb 26, 2016- -
Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 08, 2020This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with von Hippel-Lindau disease (PMID: 23298237, 7987306). This variant is also known as Tyr256Ter in the literature. ClinVar contains an entry for this variant (Variation ID: 223233). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Leu188 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7563486, 8772572, 7987306, 23772956, 19228690). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change results in a premature translational stop signal in the VHL gene (p.Tyr185*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acids of the VHL protein. -
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsSep 22, 2019The p.Y185* pathogenic mutation (also known as c.555C>G), located in coding exon 3 of the VHL gene, results from a C to G substitution at nucleotide position 555. This changes the amino acid from a tyrosine to a stop codon within coding exon 3. This mutation has been detected in multiple VHL patients (Crossey PA et al. Hum. Mol. Genet. 1994 Aug;3(8):1303-8; Zbar B et al. Hum. Mutat. 1996;8(4):348-57; Stolle C et al. Hum. Mutat. 1998;12(6):417-23). In addition, this mutation was detected as a somatic mutation in a primary sporadic renal cell cancer (Whaley JM et al. Am. J. Hum. Genet. 1994 Dec;55(6):1092-102). Of note, this alteration has also been designated as 768C>G and Tyr256Ter in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.62
D
BayesDel_noAF
Pathogenic
0.41
CADD
Uncertain
24
DANN
Benign
0.97
Eigen
Benign
-0.22
Eigen_PC
Benign
-0.52
FATHMM_MKL
Benign
0.62
D
Vest4
0.88
GERP RS
-5.0

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: rs864622109; hg19: chr3-10191562; COSMIC: COSV56542593; API