rs869025652

Variant names:

• chr3-10146607-AGC-A
• rs869025652
• NM_000551.4:c.435_436delGC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000551.4(VHL):​c.435_436delGC​(p.Gln145HisfsTer28) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q145Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.98
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• von Hippel-Lindau disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal recessive secondary polycythemia not associated with VHL gene

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• Chuvash polycythemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 148 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-10146607-AGC-A is Pathogenic according to our data. Variant chr3-10146607-AGC-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 223210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.435_436delGC	p.Gln145HisfsTer28	frameshift_variant	Exon 2 of 3	ENST00000256474.3	NP_000542.1
VHL	NR_176335.1	n.764_765delGC		non_coding_transcript_exon_variant	Exon 3 of 4
VHL	NM_001354723.2	c.*18-3179_*18-3178delGC		intron_variant	Intron 2 of 2		NP_001341652.1
VHL	NM_198156.3	c.341-3179_341-3178delGC		intron_variant	Intron 1 of 1		NP_937799.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.435_436delGC	p.Gln145HisfsTer28	frameshift_variant	Exon 2 of 3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:1

Feb 26, 2016

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Pathogenic:1

Jan 25, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. A different truncation (p.Arg161*) that lies downstream of this variant has been determined to be pathogenic (PMID: 19602254, 18446368, 24301059, 14722919, 24206762). Additionally, this truncation disrupts a significant portion of the VHL elongin binding domain (PMID: 14987375), which is required for protein stability and tumor suppressive activity (PMID: 10900011). Experimental studies have shown that missense substitutions in this domain (p.Arg161Gln, p.Cys162Trp, p.Arg167Gly, p.Arg167Trp, p.Arg167Gln) impair protein function in vitro (PMID: 25371412, 21715564, 17350623, 19602254, 15574766, 19030229, 19252526, 14973063), indicating that the amino acid residues disrupted by this truncating variant are important for protein function. This sequence change results in a premature translational stop signal in the VHL gene (p.Gln145Hisfs*28). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 69 amino acids of the VHL protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a family affected with von Hippel-Lindau syndrome (PMID: 7977367). This variant is also known as c.648_649delGC in the literature. ClinVar contains an entry for this variant (Variation ID: 223210). -

not provided Pathogenic:1

Oct 03, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The VHL c.435_436del (p.Gln145Hisfs*28) variant alters the translational reading frame of the VHL mRNA and creates a premature stop codon near the terminal region of the VHL gene where it is not expected to trigger nonsense-mediate decay of the affected transcript. However the resulting disruption of approximately 32% of the coding sequences of the VHL gene is predicted to negatively impact protein structure or function. This variant has been reported in the published literature in at least one individual with von Hippel-Lindau syndrome (PMID: 7977367 (1994)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.0
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs869025652; hg19: chr3-10188291;