3-10149871-C-G

Variant names:

• chr3-10149871-C-G
• rs5030823
• NM_000551.4:c.548C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000551.4(VHL):​c.548C>G​(p.Ser183Trp) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S183L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 4.48
• Publications: 25 publications found

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]

VHL Gene-Disease associations (from GenCC):

• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• von Hippel-Lindau disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal recessive secondary polycythemia not associated with VHL gene

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• Chuvash polycythemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000287086 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 31 uncertain in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.548C>G	p.Ser183Trp	missense_variant	Exon 3 of 3	ENST00000256474.3	NP_000542.1
VHL	NM_198156.3	c.425C>G	p.Ser142Trp	missense_variant	Exon 2 of 2		NP_937799.1
VHL	NR_176335.1	n.877C>G		non_coding_transcript_exon_variant	Exon 4 of 4
VHL	NM_001354723.2	c.*102C>G		3_prime_UTR_variant	Exon 3 of 3		NP_001341652.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.548C>G	p.Ser183Trp	missense_variant	Exon 3 of 3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pheochromocytoma Pathogenic:1

Dec 01, 2015

Endocrinology Clinic, Seth G.S. Medical College

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

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

Apr 21, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 sequence change replaces serine with tryptophan at codon 183 of the VHL protein (p.Ser183Trp). The serine residue is moderately conserved and there is a large physicochemical difference between serine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with pheochromocytoma (PMID: 27539324). ClinVar contains an entry for this variant (Variation ID: 219158). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.1	M;.
PhyloP100		4.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0020	.;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;D
Vest4		0.85
MutPred		0.61		Loss of disorder (P = 0.0064);.;
MVP		1.0
MPC		1.3
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.92
gMVP		0.85
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs5030823; hg19: chr3-10191555;