rs869025618

Positions:

• chr3-10142061-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000551.4(VHL):​c.214T>C​(p.Ser72Pro) 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. S72F) has been classified as Uncertain significance.

• 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: 0.404

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 14 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871
• PP5: Variant 3-10142061-T-C is Pathogenic according to our data. Variant chr3-10142061-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 223163.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.214T>C	p.Ser72Pro	missense_variant	1/3	ENST00000256474.3
VHL	NM_001354723.2	c.214T>C	p.Ser72Pro	missense_variant	1/3
VHL	NM_198156.3	c.214T>C	p.Ser72Pro	missense_variant	1/2
VHL	NR_176335.1	n.284T>C		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.214T>C	p.Ser72Pro	missense_variant	1/3	1	NM_000551.4	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

Likely 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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 01, 2020

Experimental studies have shown that this variant affects VHL protein function (PMID: 21715564). For these reasons, this variant has been classified as Pathogenic. 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. This variant has been observed in individual(s) with von Hippel Lindau syndrome (PMID: 17024664, 25952756, Invitae). ClinVar contains an entry for this variant (Variation ID: 223163). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with proline at codon 72 of the VHL protein (p.Ser72Pro). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and proline. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2016

The p.S72P variant (also known as c.214T>C), located in coding exon 1 of the VHL gene, results from a T to C substitution at nucleotide position 214. The serine at codon 72 is replaced by proline, an amino acid with similar properties. This variant was reported in two suspected VHL families with clinical features including retinal angioma and cerebellar hemangioblastoma (Ong KR et al. Hum. Mutat. 2007 Feb; 28(2):143-9). It was also reported in an Indian female diagnosed with VHL, who had multi-cystic pancreatic lesions, central nervous system hemangioblastoma, and a family history of VHL (Vikkath N et al. Fam. Cancer 2015 Dec; 14(4):585-94). In one functional study, this alteration's interactions with hypoxia inducible factors (HIF), which affect protein stability, were similar to that of a known VHL mutant (Rechsteiner MP et al. Cancer Res. 2011 Aug; 71(16):5500-11). 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 6375 samples (12750 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.02% (greater than 12000 alleles tested) in our clinical cohort. This amino acid position is well 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.035
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.72	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.1	D;N
REVEL	Pathogenic	0.72
Sift	Benign	0.080	.;T
Sift4G	Benign	0.16	T;T
Polyphen		0.99	D;D
Vest4		0.85
MutPred		0.71		Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);
MVP		1.0
MPC		1.1
ClinPred		0.96	D
GERP RS		2.8
Varity_R		0.97
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: rs869025618; hg19: chr3-10183745; COSMIC: COSV56544742; COSMIC: COSV56544742;