3-10142187-G-C

Position:

• chr3-10142187-G-C

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.340G>C​(p.Gly114Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G114C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL NM_000551.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.53

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a region_of_interest Involved in binding to CCT complex (size 55) in uniprot entity VHL_HUMAN there are 32 pathogenic changes around while only 1 benign (97%) 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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 3-10142187-G-C is Pathogenic according to our data. Variant chr3-10142187-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 223193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.340G>C	p.Gly114Arg	missense_variant, splice_region_variant	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.340G>C	p.Val114Leu	missense_variant, splice_region_variant	1/3		NP_001341652.1
VHL	NM_198156.3	c.340G>C	p.Val114Leu	missense_variant, splice_region_variant	1/2		NP_937799.1
VHL	NR_176335.1	n.410G>C		splice_region_variant, non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.340G>C	p.Gly114Arg	missense_variant, splice_region_variant	1/3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 06, 2023	This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 22825683]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 22265326, 34036514, 19464396, 12202531, 8956040]. -
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

Labcorp Genetics (formerly Invitae), Labcorp

Sep 26, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 114 of the VHL protein (p.Gly114Arg). This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with von Hippel-Lindau syndrome (PMID: 7728151, 12202531, 19464396, 27527340). ClinVar contains an entry for this variant (Variation ID: 223193). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

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	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.88
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.91		Loss of sheet (P = 0.007);
MVP		1.0
MPC		1.2
ClinPred		0.98	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.85
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.31		Position offset: 46
DS_DL_spliceai		0.61		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869025636; hg19: chr3-10183871; COSMIC: COSV56553319; COSMIC: COSV56553319;