rs397516442
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000551.4(VHL):c.408del(p.Phe136LeufsTer23) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
VHL
NM_000551.4 frameshift
NM_000551.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.18
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 3-10146578-AT-A is Pathogenic according to our data. Variant chr3-10146578-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 43601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VHL | NM_000551.4 | c.408del | p.Phe136LeufsTer23 | frameshift_variant | 2/3 | ENST00000256474.3 | |
VHL | NM_001354723.2 | c.*18-3206del | intron_variant | ||||
VHL | NM_198156.3 | c.341-3206del | intron_variant | ||||
VHL | NR_176335.1 | n.737del | non_coding_transcript_exon_variant | 3/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VHL | ENST00000256474.3 | c.408del | p.Phe136LeufsTer23 | frameshift_variant | 2/3 | 1 | NM_000551.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
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
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 13, 2014 | The p.Phe136fs variant in VHL has been reported as a somatic change occurring in renal cell carcinoma (Brauch 1999, Brauch 2004, Houweligen 2005, Banks 2006, Fo rmenti 2011). It has also been identified by our laboratory as a heterozygous g ermline variant in 1 individual with VHL and segregated with disease in 1 affect ed relative, although 1 obligate carrier was apparently unaffected. This framesh ift variant is predicted to alter the protein?s amino acid sequence beginning at position 136 and lead to a premature termination codon 23 amino acids downstrea m. This alteration is then predicted to lead to a truncated or absent protein. H eterozygous loss of function of the VHL gene is an established disease mechanism in VHL. In summary, this variant meets our criteria to be classified as pathoge nic for autosomal dominant VHL. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 25, 2022 | Variant summary: VHL c.408delT (p.Phe136LeufsX23) 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 251496 control chromosomes (gnomAD). c.408delT has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome (e.g. Banks_2006, Krauss_2018, Aronoff_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 22, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
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