rs869025648

Positions:

• chr3-10146587-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 10P and 2B. PM2 PP5_Very_Strong BP4 BP7

The NM_000551.4(VHL):​c.414A>G​(p.Pro138=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 synonymous
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: -1.60

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-10146587-A-G is Pathogenic according to our data. Variant chr3-10146587-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 223206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58). . Strength limited to SUPPORTING due to the PP5.
• BP7: Synonymous conserved (PhyloP=-1.6 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.414A>G	p.Pro138=	synonymous_variant	2/3	ENST00000256474.3
VHL	NM_001354723.2	c.*18-3200A>G		intron_variant
VHL	NM_198156.3	c.341-3200A>G		intron_variant
VHL	NR_176335.1	n.743A>G		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.414A>G	p.Pro138=	synonymous_variant	2/3	1	NM_000551.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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	literature only	OMIM	Mar 05, 2020	- -
Likely 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	Dec 01, 2021	Variant summary: VHL c.414A>G alters a non-conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, at least two publication reports experimental evidence that this variant affects mRNA splicing (Flores_2019, Liu_2020). The variant was absent in 251496 control chromosomes. c.414A>G has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome (Flores_2019, Liu_2020). These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 04, 2018

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this silent change causes an increase of the alternative VHL transcript with skipping of exon 2 in both patient-derived cells and minigene assays (PMID: 29891534). This variant has been observed to segregate with von Hippel-Lindau (VHL) syndrome-associated tumors in several families (PMID: 29891534). This variant has also been observed in individuals with a personal and/or family history of VHL syndrome-associated tumors (Invitae). This variant is also known as P138P in the literature. ClinVar contains an entry for this variant (Variation ID: 223206). This variant is not present in population databases (ExAC no frequency). This sequence change affects codon 138 of the VHL mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the VHL protein. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 28, 2021

Published functional studies demonstrate a damaging effect: skipping of exon 2 resulting in increased expression of the isoform lacking exon 2 and an increased expression of target genes (Lenglet 2018, Flores 2019, Liu 2020); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29891534, 30946460, 32106822, 33362715, 25825477, 33151962) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2021

The c.414A>G pathogenic mutation (also known as p.P138P), located in coding exon 2 of the VHL gene, results from an A to G substitution at nucleotide position 414. This nucleotide substitution does not change the proline at codon 138. This alteration has been identified in multiple individuals affected with pheochromocytomas, paragangliomas and/or von Hippel-Lindau syndrome (Ambry internal data, Ambry personal communication; Lenglet M et al. Blood. 2018 Aug;132:469-483; Flores SK et al. J Clin Endocrinol Metab, 2019 Apr;:; Liu F et al. BMC Med Genet, 2020 02;21:42; Ma X et al. Front Endocrinol (Lausanne), 2020 Dec;11:574662; Yonamine M et al. Cancers (Basel), 2021 Aug;13:). RT-PCR analysis of patient samples and mini gene assays show this alteration leads to skipping of exon 2 (Lenglet M et al. Blood. 2018 Aug;132:469-483) and internal RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This nucleotide position is poorly conserved in available vertebrate species. 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_noAF	Benign	-0.58
CADD	Benign	4.6
DANN	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs869025648; hg19: chr3-10188271;