rs5030823

Positions:

• chr3-10149871-C-A
• chr3-10149871-C-G
• chr3-10149871-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000551.4(VHL):​c.548C>A​(p.Ser183*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.48

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-10149871-C-A is Pathogenic according to our data. Variant chr3-10149871-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.548C>A	p.Ser183*	stop_gained	3/3	ENST00000256474.3	NP_000542.1
VHL	NM_198156.3	c.425C>A	p.Ser142*	stop_gained	2/2		NP_937799.1
VHL	NM_001354723.2	c.*102C>A		3_prime_UTR_variant	3/3		NP_001341652.1
VHL	NR_176335.1	n.877C>A		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.548C>A	p.Ser183*	stop_gained	3/3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 26, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 17, 2022	Variant summary: VHL c.548C>A (p.Ser183X) results in a premature termination codon in the last exon that is not expected to cause nonsense mediated decay (NMD), but removes a part of the 213 amino acid long protein, eliminating a portion of the alpha domain (amino acids 156-204; IPR024048). Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251414 control chromosomes (gnomAD). c.548C>A has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome (e.g. Glasker_1999, Erlic_2010, Reich_2021). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 17, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 05, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the VHL protein in which other variant(s) (p.Leu188) have been determined to be pathogenic (PMID: 7563486, 7987306, 8772572, 11331612, 16452184, 18567581, 23772956). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 2215). This variant is also known as c.761C>A. This premature translational stop signal has been observed in individuals with von Hippel-Lindau (VHL) syndrome (PMID: 8707293, 10567493, 11309459). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser183*) in the VHL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 31 amino acid(s) of the VHL protein. -

Papillary renal cell carcinoma type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1995

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 28, 2022

The p.S183* pathogenic mutation (also known as c.548C>A), located in coding exon 3 of the VHL gene, results from a C to A substitution at nucleotide position 548. This changes the amino acid from a serine to a stop codon within coding exon 3. This alteration has been reported in multiple individuals with von Hippel-Lindau disease (Whaley JM et al. Am J Hum Genet, 1994 Dec;55:1092-102; Hes FJ et al. Clin Genet, 2007 Aug;72:122-9; Dandanell M et al. BMC Med Genet, 2012 Jul;13:54; Pilotto E et al. Cancers (Basel), 2021 Dec;14:). Of note, this alteration is also referred to as "761C>A" in the literature. This alteration occurs at the 3' terminus of the VHL gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 31 amino acids of the protein. However, premature stop codons are typically deleterious in nature, the impacted region is critical for protein function, and a significant portion of the protein is affected (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.75	D
Vest4		0.92
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs5030823; hg19: chr3-10191555; COSMIC: COSV56548927;