rs1553620312

Positions:

• chr3-10149803-G-GCGATGCCTCCAGGTTGTC

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4 PP5

The NM_000551.4(VHL):​c.483_500dup​(p.Cys162_Arg167dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E160E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 1.16

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 7 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000551.4.
• PP5: Variant 3-10149803-G-GCGATGCCTCCAGGTTGTC is Pathogenic according to our data. Variant chr3-10149803-G-GCGATGCCTCCAGGTTGTC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 480846.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.483_500dup	p.Cys162_Arg167dup	inframe_insertion	3/3	ENST00000256474.3
VHL	NM_198156.3	c.360_377dup	p.Cys121_Arg126dup	inframe_insertion	2/2
VHL	NM_001354723.2	c.*37_*54dup		3_prime_UTR_variant	3/3
VHL	NR_176335.1	n.812_829dup		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.483_500dup	p.Cys162_Arg167dup	inframe_insertion	3/3	1	NM_000551.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 30, 2021

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the alpha domain of the VHL protein, which is required for interaction with Elongin C (PMID: 10205047). While functional studies have not been performed to directly test the effect of this variant on VHL protein function, this suggests that disruption of this region of the protein is causative of disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with clinical features of von Hippel-Lindau syndrome (Invitae, external communication). ClinVar contains an entry for this variant (Variation ID: 480846). This variant is not present in population databases (ExAC no frequency). This variant, c.483_500dup, results in the insertion of 6 amino acid(s) to the VHL protein (p.Cys162_Arg167dup), but otherwise preserves the integrity of the reading frame. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 02, 2017

The c.483_500dup18 pathogenic mutation (also known as p.C162_R167dup), located in coding exon 3 of the VHL gene, results from an in-frame duplication of 18 nucleotides at nucleotide positions 483 to 500. This results in the duplication of 6 extra residues (CLQVVR) between codons 162 and 167. Based on internal structural assessment, this alteration inhibits elongin binding (Van Molle I et al. Chem. Biol. 2012 Oct;19(10):1300-12). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Von Hippel-Lindau syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553620312; hg19: chr3-10191487;