chr3-10149804-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000551.4(VHL):c.481C>T(p.Arg161Ter) 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 Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
VHL
NM_000551.4 stop_gained
NM_000551.4 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 1.16
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.
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 29 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-10149804-C-T is Pathogenic according to our data. Variant chr3-10149804-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10149804-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| VHL | NM_000551.4 | c.481C>T | p.Arg161Ter | stop_gained | 3/3 | ENST00000256474.3 | NP_000542.1 | |
| VHL | NM_198156.3 | c.358C>T | p.Arg120Ter | stop_gained | 2/2 | NP_937799.1 | ||
| VHL | NM_001354723.2 | c.*35C>T | 3_prime_UTR_variant | 3/3 | NP_001341652.1 | |||
| VHL | NR_176335.1 | n.810C>T | non_coding_transcript_exon_variant | 4/4 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| VHL | ENST00000256474.3 | c.481C>T | p.Arg161Ter | stop_gained | 3/3 | 1 | NM_000551.4 | ENSP00000256474 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome
GnomAD4 genome
Cov.:
32
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Von Hippel-Lindau syndrome Pathogenic:5
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1995 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 22, 2019 | Variant summary: VHL c.481C>T (p.Arg161X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251440 control chromosomes. c.481C>T has been extensively reported in the literature spanning over two decades to co-segregate with disease among multiple affected individuals from families with Von Hippel-Lindau Syndrome (example, Loeb_1994, Zbar_1996, Maher_1996, Li_1998, Cybulski_2002, Ruiz-Llorente_2004, Gallou_2004). These data indicate that the variant is very likely to be associated with disease. No experimental evidence demonstrating an impact on protein function was ascertained during this review. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 16, 2007 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Feb 26, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genomics Labs, University Health Network | May 04, 2018 | - - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 07, 2023 | Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 53 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21362373, 26514359, 23070752, 9829911, 12114495, 10408776, 21972040, 8956040, 25867206, 27527340, 7987306, 25720320, 24581539, 18446368, 9829912, 19574279, 11409863, 19996202, 28630796, 14987375, 9681856, 17661816, 11309459, 20064270, 16572651, 28849724, 7987327, 28469506, 30787465, 33720516, 20233476, 32782288, 32974018) - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 16, 2018 | The VHL c.481C>T; p.Arg161Ter variant (rs5030818), also known as c.694C>T for traditional nomenclature, is reported multiple times in the literature in association with von Hippel-Lindau disease (see Cybulski 2002, Glavac 1996, Nordstrom-O'Brien 2010, Stolle 1998, Zbar 1996). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 2217), and it is absent from the general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-medicated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Cybulski C et al. Germline mutations in the von Hippel-Lindau (VHL) gene in patients from Poland: disease presentation in patients with deletions of the entire VHL gene. J Med Genet. 2002 Jul;39(7):E38. Glavac D et al. Mutations in the VHL tumor suppressor gene and associated lesions in families with von Hippel-Lindau disease from central Europe. Hum Genet. 1996 Sep;98(3):271-80. Nordstrom-O'Brien M et al. Genetic analysis of von Hippel-Lindau disease. Hum Mutat. 2010 May;31(5):521-37. Stolle C et al. Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum Mutat. 1998;12(6):417-23. Zbar B et al. Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat. 1996;8(4):348-57. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 28, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Familial infantile myasthenia Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Neuromuscular Department, Shariati Hospital, Tehran University of Medical Sciences | Dec 27, 2017 | - - |
Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 29, 2023 | This sequence change creates a premature translational stop signal (p.Arg161*) in the VHL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 53 amino acid(s) of the VHL protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with von Hippel-Lindau syndrome (PMID: 7987306, 8956040, 9452032, 9829911, 9829912, 10567493, 12114495, 14722919, 15300849, 18446368, 19270817, 21362373, 24206762, 24301059, 25867206). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as c.694C>T. ClinVar contains an entry for this variant (Variation ID: 2217). This variant disrupts the p.Arg161 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7728151, 9829911, 12000816, 14767570, 15300849, 20120764, 21362373, 23842656, 24707167). 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. - |
Papillary renal cell carcinoma type 1 Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Jul 14, 2015 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 17, 2023 | The p.R161* pathogenic mutation (also known as c.481C>T) located in coding exon 3 of the VHL gene, results from a C to T substitution at nucleotide position 481. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation has been reported in several individuals with personal and family histories of Von Hippel-Lindau (VHL) syndrome (Cho HJ et al. J Korean Med Sci. 2009 Feb;24:77-83; Siu WK et al. Chin. Med. J. 2011 Jan;124:237-41; Zbar B et al. Hum. Mutat. 1996;8:348-57; Papathomas TG et al. Mod. Pathol. 2015 Jun;28:807-21; Wong M et al. Chin J Cancer. 2016 Aug;35:79; Sriphrapradang C et al. Clin Med Insights Endocrinol Diabetes. 2017 Apr;10:1179551417705122). A 48 year old male with bilateral renal clear cell carcinoma and a clinical diagnosis of VHL was found to be a mosaic carrier of this pathogenic mutation (Coppin L et al. Eur. J. Hum. Genet. 2014 Sept;22:1149-52). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
MutationTaster
Benign
D;D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at