3-10142167-G-C

Variant names:

• chr3-10142167-G-C
• rs193922609
• NM_000551.4:c.320G>C

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.320G>C​(p.Arg107Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R107G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• 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 18 ACMG points.

• PM1: In a region_of_interest Involved in binding to CCT complex (size 55) in uniprot entity VHL_HUMAN there are 32 pathogenic changes around while only 1 benign (97%) 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 chr3-10142166-C-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 3-10142167-G-C is Pathogenic according to our data. Variant chr3-10142167-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10142167-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.320G>C	p.Arg107Pro	missense_variant	Exon 1 of 3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.320G>C	p.Arg107Pro	missense_variant	Exon 1 of 3		NP_001341652.1
VHL	NM_198156.3	c.320G>C	p.Arg107Pro	missense_variant	Exon 1 of 2		NP_937799.1
VHL	NR_176335.1	n.390G>C		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.320G>C	p.Arg107Pro	missense_variant	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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:2

Feb 26, 2016

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: VHL c.320G>C (p.Arg107Pro) results in a non-conservative amino acid change located in the beta domain (IPR024053) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 221140 control chromosomes (gnomAD). c.320G>C has been reported in the literature in individuals affected with Von Hippel-Lindau Syndrome (e.g., Stolle_1998, Rocha_2003, Ricketts_2015, Dallagnol_2023). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36625343, 22683710, 18836774, 26484545, 12624160, 9829911, 19996202). Additionally, different missense variants affecting the same codon, namely c.319C>G (p.Arg107Gly) and c.320G>A (p.Arg107His), have been reported in the literature in many individuals affected with VHL-related disorders (PMIDs: 12000816, 21362373, 33720516, 19336503, 12202531, 32739800). ClinVar contains an entry for this variant (Variation ID: 36900). Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Apr 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 107 of the VHL protein (p.Arg107Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of von Hippel-Lindau (VHL) syndrome (PMID: 9829911, 12624160; Invitae). This variant is also known as 533G>C. ClinVar contains an entry for this variant (Variation ID: 36900). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg107 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 19336503, 21362373, 22799452), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

May 25, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.533G>C, Arg178Pro, and Arg148Pro; This variant is associated with the following publications: (PMID: 12624160, 22825683, 9829911, 20151405, 22683710, 9143408, 32860304) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 17, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R107P pathogenic mutation (also known as c.320G>C), located in coding exon 1 of the VHL gene, results from a G to C substitution at nucleotide position 320. The arginine at codon 107 is replaced by proline, an amino acid with dissimilar properties. This alteration has been identified in numerous families meeting diagnostic criteria for von Hippel-Lindau (VHL) disease that have been affected with lesions such as CNS hemangioblastoma, retinal angioma, renal cell carcinoma, pancreatic and renal cysts, and pheochromocytoma (Stolle et al. Hum Mutat. 1998;12(6): 417-23; Rocha et al. J Med Genet. 2003;40(3): e31; Ambry Internal Data). Furthermore, three other mutations (p.R107C, p.R107H and p.R107G) at the same codon have been associated with VHL and pheochromocytoma. 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 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	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.79	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.3	D;D
REVEL	Pathogenic	0.88
Sift	Benign	0.037	.;D
Sift4G	Uncertain	0.026	D;D
Polyphen		1.0	D;D
Vest4		0.83
MutPred		0.87		Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);
MVP		1.0
MPC		1.2
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.99
gMVP		0.99

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; COSMIC: COSV56549138; COSMIC: COSV56549138;