3-10146561-G-T

Position:

• chr3-10146561-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000551.4(VHL):​c.388G>T​(p.Val130Phe) variant causes a missense change involving the alteration of a 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V130I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.67

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 11 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, 11 uncertain 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 chr3-10146561-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 2229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 3-10146561-G-T is Pathogenic according to our data. Variant chr3-10146561-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 496061.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}. Variant chr3-10146561-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.388G>T	p.Val130Phe	missense_variant	2/3	ENST00000256474.3
VHL	NM_001354723.2	c.*18-3226G>T		intron_variant
VHL	NM_198156.3	c.341-3226G>T		intron_variant
VHL	NR_176335.1	n.717G>T		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.388G>T	p.Val130Phe	missense_variant	2/3	1	NM_000551.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 09, 2016	Variant summary: VHL c.388G>T variant affects a conserved nucleotide, resulting in amino acid change from Val to Phe. 3/3 in-silico tools predict damaging outcome for this variant (SNPs&GO not captured due to low reliability index; no prediction for SIFT). This variant has been reported in at least 7 VHL patients and was not found in 121412 control chromosomes. Functional studies showed this variant affect the stabilization of HIF1a and HIF2a by VHL (Rechsteiner_2011). In addition, variants affecting same amino acid position (p.Val130Ile and p.Val130Leu), are associated with VHL. Taken together, this variant was classified as pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 01, 2018	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 11, 2024

The p.V130F pathogenic mutation (also known as c.388G>T), located in coding exon 2 of the VHL gene, results from a G to T substitution at nucleotide position 388. The valine at codon 130 is replaced by phenylalanine, an amino acid with highly similar properties. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant has been reported in patients and families who met clinical criteria for von Hippel-Lindau syndrome (VHL) (Rocha JC et al. J Med Genet, 2003 Mar;40:e31; Hes FJ et al. Clin Genet, 2007 Aug;72:122-9; Zhou J et al. Pathol Int, 2010 Jun;60:452-8; Dallagnol TN et al. Mol Genet Genomic Med, 2023 Apr;11:e2136). Additionally, another alteration at the same codon, p.V130L (c.388G>C), has also been reported in multiple unrelated patients and families meeting diagnostic criteria for VHL syndrome (Zbar B et al. Hum Mutat. 1996;8(4):348-57; Dollfus H et al. Invest. Ophthalmol. Vis. Sci. 2002 Sep;43(9):3067-74; Gallou C et al. Hum. Mutat. 2004 Sep;24(3):215-24; Wang X et al. Urology. 2014 Mar;83(3):675.e1-5; Ambry internal data). 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	0.96
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.97
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.89		Loss of sheet (P = 0.0357);
MVP		1.0
MPC		1.2
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.96
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs104893830; hg19: chr3-10188245; COSMIC: COSV56543368;