rs397516442

Positions:

• chr3-10146578-AT-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PS4_Supporting PM2_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
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• 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]

VHL (HGNC:):

ACMG classification

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
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

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

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	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: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs397516442; hg19: chr3-10188262;