rs397516442

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PS4_SupportingPM2_Supporting

This summary comes from the ClinGen Evidence Repository: The variant NM_000551.4(VHL):c.408del (p.Phe136fs) is a frameshift variant in a biologically relevant exon, altering the sequence starting at amino acid 136 and truncating 25 amino acids downstream. It is predicted to cause nonsense mediated decay (though not proven) and is in a critical domain (first beta domain, 63-155) of the protein (PVS1). Aronoff et al reports 5 affected family members with this variant. Proband III-I meets Danish criteria with pancreatic cyst or tumor, cerebellar haemangioblastoma and first degree member affected (1 point, PS4_Supporting. PMID:29437867). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA020343/MONDO:0008667/078

Frequency

Genomes: not found (cov: 32)

Consequence

VHL
NM_000551.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:4

Conservation

PhyloP100: 6.18
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 10 ACMG points.

PVS1
For more information check the summary or visit ClinGen Evidence Repository.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
VHLNM_000551.4 linkuse as main transcriptc.408delT p.Phe136fs frameshift_variant 2/3 ENST00000256474.3 NP_000542.1 P40337-1A0A024R2F2
VHLNM_001354723.2 linkuse as main transcriptc.*18-3206delT intron_variant NP_001341652.1
VHLNM_198156.3 linkuse as main transcriptc.341-3206delT intron_variant NP_937799.1 P40337-2A0A0S2Z4K1
VHLNR_176335.1 linkuse as main transcriptn.737delT non_coding_transcript_exon_variant 3/4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
VHLENST00000256474.3 linkuse as main transcriptc.408delT p.Phe136fs frameshift_variant 2/31 NM_000551.4 ENSP00000256474.3 P40337-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:3
Pathogenic, reviewed by expert panelcurationClinGen VHL Variant Curation Expert Panel, ClinGenJun 25, 2024The variant NM_000551.4(VHL):c.408del (p.Phe136fs) is a frameshift variant in a biologically relevant exon, altering the sequence starting at amino acid 136 and truncating 25 amino acids downstream. It is predicted to cause nonsense mediated decay (though not proven) and is in a critical domain (first beta domain, 63-155) of the protein (PVS1). Aronoff et al reports 5 affected family members with this variant. Proband III-I meets Danish criteria with pancreatic cyst or tumor, cerebellar haemangioblastoma and first degree member affected (1 point, PS4_Supporting. PMID:29437867). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 25, 2022Variant 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. -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 13, 2014The 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. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesNov 22, 2016- -

Computational scores

Source: dbNSFP v4.3

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Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
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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: rs397516442; hg19: chr3-10188262; API