chr3-10142124-G-A

Variant names:

• chr3-10142124-G-A
• rs5030808
• NM_000551.4:c.277G>A

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.277G>A​(p.Gly93Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,448,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 6.04

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 chain von Hippel-Lindau disease tumor suppressor (size 212) in uniprot entity VHL_HUMAN there are 96 pathogenic changes around while only 8 benign (92%) in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 3-10142124-G-A is Pathogenic according to our data. Variant chr3-10142124-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10142124-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.277G>A	p.Gly93Ser	missense_variant	Exon 1 of 3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.277G>A	p.Gly93Ser	missense_variant	Exon 1 of 3		NP_001341652.1
VHL	NM_198156.3	c.277G>A	p.Gly93Ser	missense_variant	Exon 1 of 2		NP_937799.1
VHL	NR_176335.1	n.347G>A		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.277G>A	p.Gly93Ser	missense_variant	Exon 1 of 3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448564 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 721096

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000244

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:2

Dec 15, 2021

Clinical Genomics Labs, University Health Network

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 26, 2016

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Chuvash polycythemia Pathogenic:1

Nov 30, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pheochromocytoma Pathogenic:1

May 09, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Sep 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 93 of the VHL protein (p.Gly93Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with von Hippel-Lindau (VHL) syndrome (PMID: 8707293, 9329368, 12000816, 17661816, 17922902). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as c.490G>A. ClinVar contains an entry for this variant (Variation ID: 2237). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt VHL protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Aug 05, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with VHLS and/or pheochromocytoma and has been reported to occur de novo in multiple individuals. This variant is also referred to as c.490G>A in published literature. Polyphen and MutationTaster predict this amino acid change may be damaging to the protein. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 05, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G93S pathogenic mutation (also known as c.277G>A), located in coding exon 1 of the VHL gene, results from a G to A substitution at nucleotide position 277. The glycine at codon 93 is replaced by serine, an amino acid with similar properties. This alteration has been reported in families with Von Hippel-Lindau (VHL) with pheochromocytomas as well as in individuals with isolated pheochromocytomas (Zbar B et al. Hum Mutat. 1996;8(4):348-57; Neumann HP et al. N Engl J Med. 2002 May 9;346(19):1459-66). Of note, this alteration is also known as c.490G>A in published literature. 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. 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	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.017	D;D
Polyphen		1.0	D;D
Vest4		0.77
MutPred		0.96		Loss of glycosylation at P97 (P = 0.0728);Loss of glycosylation at P97 (P = 0.0728);
MVP		1.0
MPC		1.1
ClinPred		1.0	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
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: rs5030808; hg19: chr3-10183808; COSMIC: COSV56545729; COSMIC: COSV56545729;