NM_000551.4:c.263_265dupGGC

Variant names:

• chr3-10142109-T-TGGC
• rs1131690960
• NM_000551.4:c.263_265dupGGC

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM4_Supporting PP5_Moderate

The NM_000551.4(VHL):​c.263_265dupGGC​(p.Trp88_Leu89insArg) variant causes a disruptive inframe insertion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L89L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL NM_000551.4 disruptive_inframe_insertion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.04
• Publications: 0 publications found

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]

VHL Gene-Disease associations (from GenCC):

• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• von Hippel-Lindau disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal recessive secondary polycythemia not associated with VHL gene

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• Chuvash polycythemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 27 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 34 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 VariationId is 428805.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.263_265dupGGC	p.Trp88_Leu89insArg	disruptive_inframe_insertion	Exon 1 of 3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.263_265dupGGC	p.Trp88_Leu89insArg	disruptive_inframe_insertion	Exon 1 of 3		NP_001341652.1
VHL	NM_198156.3	c.263_265dupGGC	p.Trp88_Leu89insArg	disruptive_inframe_insertion	Exon 1 of 2		NP_937799.1
VHL	NR_176335.1	n.333_335dupGGC		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.263_265dupGGC	p.Trp88_Leu89insArg	disruptive_inframe_insertion	Exon 1 of 3	1	NM_000551.4	ENSP00000256474.3

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

Jun 01, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.0
Mutation Taster		=39/61	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1131690960; hg19: chr3-10183793;