3-10142187-G-A

Variant names:

• chr3-10142187-G-A
• rs869025636
• NM_000551.4:c.340G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000551.4(VHL):​c.340G>A​(p.Gly114Ser) 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. 2/3 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. G114R) has been classified as 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:2
• Conservation: PhyloP100: 4.53
• Publications: 28 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

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 34 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 18 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 chr3-10142187-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 223193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 3-10142187-G-A is Pathogenic according to our data. Variant chr3-10142187-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 583094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.340G>A	p.Gly114Ser	missense_variant, splice_region_variant	Exon 1 of 3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.340G>A	p.Val114Ile	missense_variant, splice_region_variant	Exon 1 of 3		NP_001341652.1
VHL	NM_198156.3	c.340G>A	p.Val114Met	missense_variant, splice_region_variant	Exon 1 of 2		NP_937799.1
VHL	NR_176335.1	n.410G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.340G>A	p.Gly114Ser	missense_variant, splice_region_variant	Exon 1 of 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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Nov 24, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine with serine at codon 114 of the VHL protein (p.Gly114Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant also falls at the last nucleotide of exon 1 of the VHL coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with von Hippel-Lindau (VHL) syndrome, or VHL-associated lesions (PMID: 20660572, 23407287, 15002726, Invitae). This variant is also known as c.553G>A in the literature. Other missense substitutions at this codon (p.Gly114Arg and p.Gly114Cys) have been reported in individuals affected with VHL syndrome (PMID: 7728151, 27527340, 7987306). This suggests that the glycine residue is critical for VHL protein function and that other missense substitutions at this position may also be pathogenic. Experimental studies have shown that while this missense change does not affect microtubule stabilization, it does exhibit disrupted microtubule turnover, reduced assembly of the VCB-Cul2 complex, and decreased HIF-1 alpha binding and ubiquitination (PMID: 11865071, 12510195, 20855504). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Sep 14, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G114S pathogenic mutation (also known as c.340G>A), located in coding exon 1 of the VHL gene, results from a G to A substitution at nucleotide position 340. The glycine at codon 114 is replaced by serine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 1 and may have some effect on normal mRNA splicing. In functional studies, this alteration was shown to reduce binding and decrease ability to ubiquinate a critical transcription factor HIF1-alpha (Hansen WJ et al. Mol Cell Biol, 2002 Mar;22:1947-60). In addition, this alteration was shown to moderately decrease microtubule regulatory functions compared to the wildtype VHL protein (Thoma CR et al. J Cell Biol, 2010 Sep;190(6):991-1003). This alteration has been reported in multiple individuals with features of VHL and/or a clinical diagnosis of VHL (Loughrey PB et al. Endocr Relat Cancer, 2022 Oct;29:R157-R172; Petenuci J et al. Clin Endocrinol (Oxf), 2021 Jul;95:117-124; Krauss T et al. Endocr Relat Cancer, 2018 Sep;25:783-793; Erlic Z et al. Endocr Relat Cancer, 2010 Dec;17:875-83). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. This amino acid position is highly conserved in available vertebrate species. In addition, as a missense substitution this is predicted to be deleterious by in silico analysis. 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	0.65
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
PhyloP100		4.5
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.81
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.68
MutPred		0.89		Loss of sheet (P = 0.007);
MVP		1.0
MPC		0.89
ClinPred		0.95	D
GERP RS		5.1
PromoterAI		-0.36	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.89
gMVP		0.91
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: 46
DS_DL_spliceai		0.33		Position offset: 0

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

Other links and lift over

dbSNP: rs869025636; hg19: chr3-10183871; COSMIC: COSV56546928;