rs5030832

chr3-10146535-A-Gchr3-10146535-A-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000551.4(VHL):c.362A>G(p.Asp121Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D121N) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.46

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 18 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, 10 uncertain in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-10146534-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2203306.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 3-10146535-A-G is Pathogenic according to our data. Variant chr3-10146535-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 223200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.362A>G	p.Asp121Gly	missense_variant	2/3	ENST00000256474.3
VHL	NM_001354723.2	c.*18-3252A>G		intron_variant
VHL	NM_198156.3	c.341-3252A>G		intron_variant
VHL	NR_176335.1	n.691A>G		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.362A>G	p.Asp121Gly	missense_variant	2/3	1	NM_000551.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461678 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727130

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 05, 2016	Variant summary: c.362A>G affects a conserved nucleotide, resulting in amino acid change from Asp to Gly. 4/4 in-silico tools predict this variant to be damaging. This variant was not found in 121412 control chromosomes. This variant has been reported in multiple VHL patients. Functional studies showed that variant retained most of the proteins abilities, including its interaction with HIF in vitro and the downstream down-regulation of gene expression controlled by HIF, as well as supporting HIF-1 ubiquitination (less than that observed for wild-type pVHL), and the interaction with elongin C. (Hansen_2002, Ruiz-Llorente_2004). However, there is also study showed that only partial interaction with elongin C is retained and the recruiting a complex containing the essential human VBCE3 ubiquitin ligase components CHL2 and ROC1 is detected (Hacker _2008). Considering all these studies were performed in vitro, the disease mechanism of this variant remains unclear. Variants D121G, D121N both are listed as disease mutation in HGMD and have been reported in multiple publications suggesting the codon 121 might be a hotspot for mutations. Taken together, this variant was classified as a Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 26, 2016	- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 11, 2020

This sequence change replaces aspartic acid with glycine at codon 121 of the VHL protein (p.Asp121Gly). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with, or with clinical features of von Hippel-Lindau syndrome (PMID: 16572651, 7977367, 9681856, 15300849, 20660572, 11409863, 8956040). ClinVar contains an entry for this variant (Variation ID: 223200). Experimental studies have shown that this missense change affects nuclear export of the VHL protein and its effect on downstream target HIF (PMID: 17967880, 11865071, 21715564). 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 disrupts the p.Asp121 amino acid residue in VHL. Other variants that disrupt this residue have been observed in affected individuals (PMID: 16142346, 25557216), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 16, 2017

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 08, 2021

The p.D121G variant (also known as c.362A>G), located in coding exon 2 of the VHL gene, results from an A to G substitution at nucleotide position 362. The aspartic acid at codon 121 is replaced by glycine, an amino acid with similar properties. This variant has been identified in multiple individuals with a clinical diagnosis or suspicion of von-Hippel-Lindau (VHL) syndrome (Ruiz-Llorente S et al. Hum Mutat, 2004 Feb;23:160-9; Erlic Z et al. Endocr Relat Cancer, 2010 Dec;17:875-83; Rasmussen A et al. J Neurosurg, 2006 Mar;104:389-94). In functional studies, this alteration was shown to decrease nuclear export of the VHL protein and to reduce ability to degrade downstream target HIF-alpha (Khacho M et al. Mol Cell Biol, 2008 Jan;28:302-14; Rechsteiner MP et al. Cancer Res, 2011 Aug;71:5500-11). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on internal structural analysis, D121G is moderately destabilizing to the local structure and more disruptive than known pathogenic variants in the region (Ambry internal data). 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
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.91
Sift4G	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.86
MutPred		0.94		Loss of sheet (P = 0.0104);
MVP		1.0
MPC		1.2
ClinPred		0.99	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs5030832; hg19: chr3-10188219; COSMIC: COSV56543093;