3-10146526-T-G

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.353T>G(p.Leu118Arg) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L118P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.18

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 hotspot region, there are 14 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 chr3-10146526-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 428807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 3-10146526-T-G is Pathogenic according to our data. Variant chr3-10146526-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 428802.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.353T>G	p.Leu118Arg	missense_variant	2/3	ENST00000256474.3
VHL	NM_001354723.2	c.*18-3261T>G		intron_variant
VHL	NM_198156.3	c.341-3261T>G		intron_variant
VHL	NR_176335.1	n.682T>G		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.353T>G	p.Leu118Arg	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

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

Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)

May 21, 2023

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 12, 2023

The p.L118R pathogenic mutation (also known as c.353T>G), located in coding exon 2 of the VHL gene, results from a T to G substitution at nucleotide position 353. The leucine at codon 118 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with VHL-related disease (Ambry internal data). This pathogenic mutation was reported as a germline mutation in a VHL family with pheochromocytomas. This study indicated that VHL gene missense mutation carriers have a higher risk of developing a pheochromocytomas than carriers of other types of VHL gene mutations (Maher ER et al. J. Med. Genet. 1996 Apr;33:328-32). Another study showed this mutation leads to a decreased affinity for the TRiC/CTT chaperonin which results in improper folding of the VHL protein (Feldman DE et al. Mol. Cell. 2003 Nov;12:1213-24). Authors of another study concurred that missense mutations in the VHL gene are associated with a higher risk of pheochromocytomas, however they divided missense mutations into two subgroups:surface missense amino acid substitution mutations (SM) and deep missense mutations (DM). Missense mutations in the SM group were found to be at a significantly higher risk for pheochromocytomas than missense mutations in the DM group. The p.L118R mutation was categorized as a DM due to its location in the protein core and the disruption of protein function (Ong KR et al. Hum. Mutat. 2007 Feb;28:143-9). Of note, this alteration is referred to as c.566T>G (p.L189R) in some literature. This alteration is predicted to be deleterious by BayesDel in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	0.90
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-4.1	D
REVEL	Pathogenic	0.88
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.94		Loss of sheet (P = 0.007);
MVP		0.99
MPC		1.3
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.98

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: rs5030830; hg19: chr3-10188210; COSMIC: COSV56546980;