rs1131690960

chr3-10142109-T-TGGC

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4_Supporting PP5_Moderate

The NM_000551.4(VHL):c.263_265dup(p.Trp88_Leu89insArg) variant causes a inframe insertion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL NM_000551.4 inframe_insertion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.04

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 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 14 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. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 3-10142109-T-TGGC is Pathogenic according to our data. Variant chr3-10142109-T-TGGC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428805.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.263_265dup	p.Trp88_Leu89insArg	inframe_insertion	1/3	ENST00000256474.3
VHL	NM_001354723.2	c.263_265dup	p.Trp88_Leu89insArg	inframe_insertion	1/3
VHL	NM_198156.3	c.263_265dup	p.Trp88_Leu89insArg	inframe_insertion	1/2
VHL	NR_176335.1	n.333_335dup		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.263_265dup	p.Trp88_Leu89insArg	inframe_insertion	1/3	1	NM_000551.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 01, 2018

The c.263_265dupGGC variant (also known as p.W88_L89insR), located in coding exon 1 of the VHL gene, results from an in-frame duplication of GGC at nucleotide positions 263 to 265, and results in the insertion of an extra arginine residue between codons 88 and 89. This alteration has been identified in unrelated individuals meeting diagnostic criteria for Von Hippel-Lindau (VHL) (Ambry internal data). Further, multiple similar non-truncating alterations in this region (p.W88R, p.W88L, p.W88C, p.L89P) have been reported in individuals satisfying established diagnostic criteria for VHL (Chen F, Hum. Mutat. 1995 ; 5(1):66-75, Kondo, et al. Hum. Mol. Genet. 1995 Dec; 4(12):2233-7, Gläsker S, J. Neurol. Neurosurg. Psychiatr. 1999 Dec; 67(6):758-62, Rocha JC, J. Med. Genet. 2003 Mar; 40(3):e31; Ong KR et al. Hum Mutat. 2007;28(2):143-149). In addition, based on internal structural assessment, this alteration results in local structural perturbation of the VHL protein fold, near the HIF1α-peptide-binding site (Min JH et al. Science, 2002 Jun;296:1886-9; Van Molle I et al. Chem. Biol., 2012 Oct;19:1300-12). The duplicated nucleotide region is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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: rs1131690960; hg19: chr3-10183793;