rs397516440

Positions:

• chr3-10142166-C-G
• chr3-10142166-C-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.319C>G​(p.Arg107Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. R107P) has been classified as Likely 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:3
• Conservation: PhyloP100: 3.24

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 chr3-10142167-G-C is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 3-10142166-C-G is Pathogenic according to our data. 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. Variant chr3-10142166-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.319C>G	p.Arg107Gly	missense_variant	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.319C>G	p.Arg107Gly	missense_variant	1/3		NP_001341652.1
VHL	NM_198156.3	c.319C>G	p.Arg107Gly	missense_variant	1/2		NP_937799.1
VHL	NR_176335.1	n.389C>G		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.319C>G	p.Arg107Gly	missense_variant	1/3	1	NM_000551.4	ENSP00000256474	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 20, 2015

The p.Arg107Gly variant in VHL has been reported as a de novo (paternity confirm ed) occurrence in 1 child with nonsyndromic pheochromocytomas (Neumann 2002). In addition, it was identified in 2 children with von Hippel-Lindau (VHL) syndrome and segregated with disease in 4 affected family members from 2 families (Siu 2 011, LMM unpublished data). Of note, other variants at this position (p.Arg107Hi s, p.Arg107Pro) have been reported in individuals with VHL, suggesting that an a lteration at this position is not tolerated. In summary, this variant meets our criteria to be classified as pathogenic for VHL in an autosomal dominant manner (http://www.partners.org/personalizedmedicine/LMM) based upon a de novo occurren ce and segregation studies. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2014

The p.R107G variant (also known as c.319C>G), located in coding exon 1 of the VHL gene, results from a C to G substitution at nucleotide position 319. The arginine at codon 107 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been previously identified in individuals with CNS hemangioblastoma and one individual with isolated pheochromocytoma (Siu WK, Chin. Med. J. 2011 Jan; 124(2):237-41. Neumann HP, N. Engl. J. Med. 2002 May; 346(19):1459-66; Ambry Internal Data). In addition, three other mutations (p.R107C, p.R107H and p.R107P) in the same codon have been associated with VHL and pheochromocytoma. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 5215 samples (10430 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.02% (greater than 4300 alleles tested) in our clinical cohort. Based on protein sequence alignment, 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 majority of available evidence to date, this variant is likely to be pathogenic. -

Von Hippel-Lindau syndrome;C0031511:Pheochromocytoma;C1837915:Chuvash polycythemia;CN074294:Nonpapillary renal cell carcinoma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	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
MutationTaster	Benign	0.96	D;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.85
Sift	Benign	0.030	.;D
Sift4G	Uncertain	0.015	D;D
Polyphen		1.0	D;D
Vest4		0.71
MutPred		0.89		Loss of methylation at R107 (P = 0.0131);Loss of methylation at R107 (P = 0.0131);
MVP		1.0
MPC		1.1
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.97
gMVP		0.96

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: rs397516440; hg19: chr3-10183850; COSMIC: COSV56548066; COSMIC: COSV56548066;