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
Consequence
NM_000551.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
VHL | NM_000551.4 | c.408delT | p.Phe136fs | frameshift_variant | 2/3 | ENST00000256474.3 | NP_000542.1 | |
VHL | NM_001354723.2 | c.*18-3206delT | intron_variant | NP_001341652.1 | ||||
VHL | NM_198156.3 | c.341-3206delT | intron_variant | NP_937799.1 | ||||
VHL | NR_176335.1 | n.737delT | non_coding_transcript_exon_variant | 3/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
VHL | ENST00000256474.3 | c.408delT | p.Phe136fs | frameshift_variant | 2/3 | 1 | NM_000551.4 | ENSP00000256474.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Von Hippel-Lindau syndrome Pathogenic:3
Pathogenic, reviewed by expert panel | curation | ClinGen VHL Variant Curation Expert Panel, ClinGen | Jun 25, 2024 | 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). - |
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. - |
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. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 22, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at