rs193922609

chr3-10142167-G-Achr3-10142167-G-Cchr3-10142167-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000551.4(VHL):c.320G>A(p.Arg107His) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R107G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.52

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 16 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000551.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-10142166-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 3-10142167-G-A is Pathogenic according to our data. Variant chr3-10142167-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 223184.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.320G>A	p.Arg107His	missense_variant	1/3	ENST00000256474.3
VHL	NM_001354723.2	c.320G>A	p.Arg107His	missense_variant	1/3
VHL	NM_198156.3	c.320G>A	p.Arg107His	missense_variant	1/2
VHL	NR_176335.1	n.390G>A		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.320G>A	p.Arg107His	missense_variant	1/3	1	NM_000551.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1446336 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 720000

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

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

Feb 26, 2016

- -

VHL-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 02, 2023

The VHL c.320G>A variant is predicted to result in the amino acid substitution p.Arg107His. This variant was reported in an individual with Von Hippel-Lindau syndrome (Dollfus et al 2002. PubMed ID: 12202531). Other missense changes at the same amino acid position, p.Arg107Pro, p.Arg107His, and p.Arg107Gly have all been reported in patients with Von Hippel-Lindau syndrome (Rocha JC et al 2003. PubMed ID: 12624160; Boedeker CC et al 2009. PubMed ID: 19336503; Stolle C et al 1998. PubMed ID: 9829911; Neumann HP et al 2002. PubMed ID: 12000816). 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

Invitae

Aug 31, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg107 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12000816, 12624160, 21362373, 22799452; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function. ClinVar contains an entry for this variant (Variation ID: 223184). This missense change has been observed in individuals with VHL-related conditions (PMID: 12202531, 19336503; external communication). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 107 of the VHL protein (p.Arg107His). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2015

The p.R107H pathogenic mutation (also known as c.320G>A), located in coding exon 1 of the VHL gene, results from a G to A substitution at nucleotide position 320. The arginine at codon 107 is replaced by histidine, an amino acid with highly similar properties.This alteration has been reported in a woman meeting clinical diagnostic criteria for VHL and segregated with disease in her family (BoedekerCC et al. JClinEndocrinolMetab. 2009 Jun;94(6):1938-44). In addition, three other alterations at the same codon (p.R107C, p.R107P and p.R107G) have been associated with VHL and pheochromocytoma(DandanellM et al.BMC Med. Genet. 2012 ; 13():54;Siu WK et al.Chin. Med. J. 2011 Jan; 124(2):237-41;StolleC et al.Hum.Mutat. 1998;12(6):417-23). Based on the available evidence to date, p.R107H is classified as a pathogenic mutation.<br /> -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	0.96	D;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.0	N;N
REVEL	Pathogenic	0.77
Sift4G	Uncertain	0.016	D;D
Polyphen		1.0	D;D
Vest4		0.48
MutPred		0.90		Loss of methylation at R107 (P = 0.0131);Loss of methylation at R107 (P = 0.0131);
MVP		1.0
MPC		1.1
ClinPred		0.97	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.90
gMVP		0.85

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: rs193922609; hg19: chr3-10183851;