rs5030648

Positions:

• chr3-10142070-ATCT-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000551.4(VHL):​c.227_229del​(p.Phe76del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000000687 in 1,454,798 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: VHL NM_000551.4 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 4.96

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 13 ACMG points.

• PM1: In a strand (size 7) in uniprot entity VHL_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 3-10142070-ATCT-A is Pathogenic according to our data. Variant chr3-10142070-ATCT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 223166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10142070-ATCT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.227_229del	p.Phe76del	inframe_deletion	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.227_229del	p.Phe76del	inframe_deletion	1/3		NP_001341652.1
VHL	NM_198156.3	c.227_229del	p.Phe76del	inframe_deletion	1/2		NP_937799.1
VHL	NR_176335.1	n.297_299del		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.227_229del	p.Phe76del	inframe_deletion	1/3	1	NM_000551.4	ENSP00000256474	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1454798 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 723838

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 03, 2019	The p.Phe76del variant in VHL has been reported in >15 individuals with clinical features of Von Hippel-Lindau syndrome and segregated with disease in >5 affected individuals from several families (Crossey 1994, Cybulski 2002, Gomy 2010, Hes 2007, Jia 2013, Lee 2016, Nordstrom-Obrien 2010, Pandit 2016, Rasmussen 2010, Wang 2018, Wong 2016, Wu 2012, Zhang 2008). It was also identified as a de novo occurrence in 1 individual, though maternity and paternity were not confirmed (Jia 2013). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 223166) and was absent from large population studies. This variant is a deletion of 1 amino acid at position 76 and is not predicted to alter the protein reading-frame. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Von Hippel- Lindau syndrome. ACMG/AMP criteria applied: PS4, PM2, PM6, PP1_Moderate, PM4_Supporting. -
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	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jul 13, 2021	ACMG classification criteria: PS4 strong, PM2 moderate, PM4 moderate, PM6 moderate, PP1 very strong -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Pathogenic, criteria provided, single submitter	curation	CIViC knowledgebase, Washington University School of Medicine	-	The inframe variant, F76del, is pathogenic for Von Hippel-Lindau Disease. EID5682 shows a large family with the variant cosegregating with affected individuals (PP1). However, confirmed de novo mutations are also described EID5340 (PS2). Both are supported by several other reports with familial and sporadic VHL and this variant. This inframe deletion is not in a repetitive region (PM4) and absent from gnomAD v2.1 (PM2). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 09, 2022	The VHL c.227_229del variant is classified as Likely Pathogenic (PS4_Moderate, PM2, PM4, PM6, PP1, PP4) The VHL c.227_229del variant results in an inframe deletion in exon 1/3. This variant has been reported in 9 unrelated individuals with a clinical presentation of von Hippel-Lindau syndrome (PMID: 7987306, 27527340, 29616089, 32179488, 33720516) (PS4_Moderate). This variant is absent from population databases (PM2). This variant is predicted to alter the length of the protein produced by this gene due to an inframe deletion variant in a nonrepeat region (PM4). This variant has been identified as a de novo variant in at least one affected patient with no family history of this condition (PMID: 8641976, 23632291) (PM6). This variant is reported to co-segregate with disease in one family (PMID: 23143947) (PP1). The clinical features of this case are highly specific for the VHL gene (PP4). This variant is in dbSNP (rs5030648), has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID:223166) and has been reported as disease-causing in HGMD (CD941805). -

VHL-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 11, 2022

The VHL c.227_229delTCT variant is predicted to result in an in-frame deletion (p.Phe76del). This variant has been previously reported in the heterozygous state in individuals or affected family members with Von Hippel-Lindau syndrome (see for example Hes et al. 2007. PubMed ID: 17661816; Ong et al. 2007. PubMed ID: 17024664, Supplementary Table S1; Nordstrom-O'Brien et al. 2010. PubMed ID: 20151405, Supplementary Table S1; Leonardi et al. 2011. PubMed ID: 21463266, Supplementary material; Wu et al. 2012. PubMed ID: 22357542; also reported with differences in the cDNA nomenclature in Wong et al. 2016. PubMed ID: 27527340; Pandit et al. 2016. PubMed ID: 27539324; Lomte et al. 2018. PubMed ID: 29124493). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2023

This variant, c.227_229del, results in the deletion of 1 amino acid(s) of the VHL protein (p.Phe76del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Hippel-Lindau syndrome (PMID: 12114495, 17661816, 18446368, 20064270, 20151405, 20567917, 22357542, 23632291, 27439424, 27527340). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 223166). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 30, 2021

In-frame deletion of 1 amino acid in a non-repeat region in the critical beta sandwich region of the beta domain (Yuen 2009); Not observed in large population cohorts (Lek 2016); In silico analysis supports a deleterious effect on protein structure/function; Also known as c.440_442del, p.(F147del); p.(F117del); This variant is associated with the following publications: (PMID: 7987306, 20064270, 20567917, 12624160, 8730290, 8634692, 9829911, 29961792, 30072823, 31528828, 27682873, 28036268, 27539324, 27527340, 27439424, 12114495, 17661816, 18446368, 20151405, 22357542, 7728151, 7553625, 8956040, 9829912, 10631138, 8641976, 7977367, 23632291, 25867206, 23011899, 11331613, 29124493, 29616089, 29748190, 32179488, 33720516, 33107222, 32003155) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 28, 2019

The c.227_229delTCT pathogenic mutation (also known as c.226_228del TTC or p.F76del) is located in coding exon 1 of the VHL gene. This pathogenic mutation results from an in-frame TCT deletion at nucleotide positions 227 to 229. This results in the in-frame deletion of a phenylalanine at codon 76. This pathogenic variant has been identified in numerous individuals and families diagnosed with VHL (Rocha J et al. J. Med. Genet. 2003 Mar; 40(3):e31; Sgambati M et al. Am. J. Hum. Genet. 2000 Jan; 66(1):84-91; Gomy I et al. Fam. Cancer. 2010 Dec; 9(4):635-42; Hes F et al. Clin. Genet. 2007 Aug; 72(2):122-9; Rasmussen A et al. BMC Med. Genet. 2010 Jan 12;11:4; Pandit R et al. Eur. J. Endocrinol. 2016 Oct;175:311-23; Wong M et al. Chin J Cancer. 2016 Aug;35:79; Wang Y et al. Oncol Lett. 2018 Apr;15:4882-4890). Molecular dynamics studies indicate that the phenyalanine at amino acid position 76, which is deleted by this alteration, plays a key role in the structural integrity of the beta-domain of the VHL protein (Limaverde-Sousa G et al. Proteins. 2013 Feb; 81(2):349-63). Of note, this pathogenic variant may be referred to as c.224_226delTCT in some literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

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: rs5030648; hg19: chr3-10183754;