rs1553619952

Positions:

• chr3-10146549-GA-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000551.4(VHL):​c.377del​(p.Asp126ValfsTer33) 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
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.28

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 3-10146549-GA-G is Pathogenic according to our data. Variant chr3-10146549-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 456565.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.377del	p.Asp126ValfsTer33	frameshift_variant	2/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.*18-3237del		intron_variant			NP_001341652.1
VHL	NM_198156.3	c.341-3237del		intron_variant			NP_937799.1
VHL	NR_176335.1	n.706del		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.377del	p.Asp126ValfsTer33	frameshift_variant	2/3	1	NM_000551.4	ENSP00000256474	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 03, 2017

This sequence change results in a premature translational stop signal in the VHL gene (p.Asp126Valfs*33). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 88 amino acids of the VHL protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with VHL-related disease. This truncation disrupts a significant portion of the VHL elongin C binding domain (PMID: 14987375), which is required for protein stability and tumor suppressive activity (PMID: 10900011). Different truncations downstream of this variant (p.Asn141Lysfs*3, p.161Arg*, deletion of exon 3) have been determined to be pathogenic (PMID: 19270817, 10567493, 7987306, 12114495, 25867206, 15300849, 9829911, 9829912, 9452032, 8956040, 21362373, 18446368, 24301059, Invitae). This suggests that deletion of this region of the VHL protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 18, 2017

For these reasons, this variant has been classified as Pathogenic. This truncation disrupts a significant portion of the VHL elongin C binding domain (PMID: 14987375), which is required for protein stability and tumor suppressive activity (PMID: 10900011). Different truncations downstream of this variant (p.Asn141Lysfs*3, p.161Arg*, deletion of exon 3) have been determined to be pathogenic (PMID: 19270817, 10567493, 7987306, 12114495, 25867206, 15300849, 9829911, 9829912, 9452032, 8956040, 21362373, 18446368, 24301059, Invitae). This suggests that deletion of this region of the VHL protein is causative of disease. This variant has not been reported in the literature in individuals with VHL-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the VHL gene (p.Asp126Valfs*33). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 88 amino acids of the VHL protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs1553619952; hg19: chr3-10188233;