rs1347416980

chr3-10146568-A-Cchr3-10146568-A-Gchr3-10146568-A-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000551.4(VHL):c.395A>C(p.Gln132Pro) 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.31

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 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 3-10146568-A-C is Pathogenic according to our data. Variant chr3-10146568-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496063.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.395A>C	p.Gln132Pro	missense_variant	2/3	ENST00000256474.3
VHL	NM_001354723.2	c.*18-3219A>C		intron_variant
VHL	NM_198156.3	c.341-3219A>C		intron_variant
VHL	NR_176335.1	n.724A>C		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.395A>C	p.Gln132Pro	missense_variant	2/3	1	NM_000551.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 09, 2016

Variant summary: The c.395A>C in VHL gene is a missense variant that involves a conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant is absent from the broad control population dataset of ExAC, suggesting this variant is not a common polymorphism. The variant has been reported in multiple affected individuals presented with von Hippel-Lindau disease, including several familial cases. The variant of interest has been reported as Pathogenic via peer-reviewed publications. Taking together, the variant was classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 05, 2016

The p.Q132P variant (also known as c.395A>C), located in coding exon 2 of the VHL gene, results from an A to C substitution at nucleotide position 395. The glutamine at codon 132 is replaced by proline, an amino acid with similar properties. This alteration was identified in a patient meeting clinical diagnostic criteria for VHL disease (Dollfus H et al. Invest. Ophthalmol. Vis. Sci., 2002 Sep;43:3067-74). In addition, this alteration was been reported in one family from the French VHL registry (Gallou C et al. Hum. Mutat., 2004 Sep;24:215-24), another family with suspected VHL (Ong KR et al. Hum. Mutat., 2007 Feb;28:143-9), and three patients with a history of CNS hemangioblastomas (Gläsker S et al. J. Neurol. Neurosurg. Psychiatr., 1999 Dec;67:758-62). 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 6503 samples (13006 alleles) with coverage at this position. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration was predicted to destabilize the HIF binding domain of pVHL by a group utilizing in silico software and database tools (Forman JR et al. Proteins, 2009 Oct;77:84-96). Of note, this alteration is also known as 608A>C in published literature. 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	0.94
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.85
Sift4G	Uncertain	0.024	D
Polyphen		0.99	D
Vest4		0.95
MutPred		0.78		Loss of sheet (P = 0.0126);
MVP		1.0
MPC		1.1
ClinPred		0.98	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.93
gMVP		0.93

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: rs1347416980; hg19: chr3-10188252; COSMIC: COSV56562793;