chr3-10141883-G-C

Position:

• chr3-10141883-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_000551.4(VHL):​c.36G>C​(p.Glu12Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000579 in 1,381,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E12K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000058 (0 hom.)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -0.128

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 Uncertain_significance. Variant got 0 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.08640897).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.36G>C	p.Glu12Asp	missense_variant	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.36G>C	p.Glu12Asp	missense_variant	1/3		NP_001341652.1
VHL	NM_198156.3	c.36G>C	p.Glu12Asp	missense_variant	1/2		NP_937799.1
VHL	NR_176335.1	n.106G>C		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.36G>C	p.Glu12Asp	missense_variant	1/3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000579 AC: 8 AN: 1381390 Hom.: 0 Cov.: 32 AF XY: 0.00000442 AC XY: 3 AN XY: 679118

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: 0.00

Gnomad4 NFE exome AF: 0.00000748

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000633 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 15, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 12 of the VHL protein (p.Glu12Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a haemangioblastoma of the central nervous system or the spinal cord (PMID: 21463266). ClinVar contains an entry for this variant (Variation ID: 419711). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt VHL protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 11, 2016

This variant is denoted VHL c.36G>C at the cDNA level, p.Glu12Asp (E12D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAG>GAC). This variant was observed in an individual with an isolated brain/spinal cord hemangioblastoma (Leonardi 2011). VHL Glu12Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glutamic Acid and Aspartic Acid share similar properties, this is considered a conservative amino acid substitution. VHL Glu12Asp occurs at a position that is not conserved and is not located in a known functional domain (Yuen 2009, UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether VHL Glu12Asp is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2023

The p.E12D variant (also known as c.36G>C), located in coding exon 1 of the VHL gene, results from a G to C substitution at nucleotide position 36. The glutamic acid at codon 12 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration was identified in a 50 year old diagnosed with a central nervous system hemangioblastoma (Leonardi E et al. Ann. Hum. Genet., 2011 Jul;75:483-96). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Von Hippel-Lindau syndrome;C0031511:Pheochromocytoma;C1837915:Chuvash polycythemia;CN074294:Nonpapillary renal cell carcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	6.3
DANN	Benign	0.93
DEOGEN2	Benign	0.31	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.086	T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.55	N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.22	N;N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	.;D
Sift4G	Benign	0.11	T;T
Polyphen		0.0	B;B
Vest4		0.080
MutPred		0.35		Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP		0.98
MPC		0.41
ClinPred		0.096	T
GERP RS		-0.074
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.6
Varity_R		0.16
gMVP		0.31

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: rs973493604; hg19: chr3-10183567;