NM_000551.4:c.46G>C

Variant names:

• chr3-10141893-G-C
• rs1060503556
• NM_000551.4:c.46G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000551.4(VHL):​c.46G>C​(p.Glu16Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,380,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. E16V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.755
• Publications: 4 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21347854).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000551.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	NM_000551.4	MANE Select	c.46G>C	p.Glu16Gln	missense	Exon 1 of 3	NP_000542.1
	VHL	NM_001354723.2		c.46G>C	p.Glu16Gln	missense	Exon 1 of 3	NP_001341652.1
	VHL	NM_198156.3		c.46G>C	p.Glu16Gln	missense	Exon 1 of 2	NP_937799.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	ENST00000256474.3	TSL:1 MANE Select	c.46G>C	p.Glu16Gln	missense	Exon 1 of 3	ENSP00000256474.3
	VHL	ENST00000345392.3	TSL:1	c.46G>C	p.Glu16Gln	missense	Exon 1 of 2	ENSP00000344757.2
	VHL	ENST00000477538.2	TSL:1	n.92G>C		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000710 AC: 1 AN: 140774 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1380528 Hom.: 0 Cov.: 32 AF XY: 0.00000147 AC XY: 1 AN XY: 678530

African (AFR) AF: 0.00 AC: 0 AN: 30822

American (AMR) AF: 0.00 AC: 0 AN: 34030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24386

East Asian (EAS) AF: 0.00 AC: 0 AN: 35300

South Asian (SAS) AF: 0.0000258 AC: 2 AN: 77480

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4042

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1069466

Other (OTH) AF: 0.0000176 AC: 1 AN: 56930

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Feb 12, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid with glutamine at codon 16 of the VHL protein (p.Glu16Gln). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a VHL-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

not provided Uncertain:1

Nov 02, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Uncertain:1

Oct 12, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E16Q variant (also known as c.46G>C), located in coding exon 1 of the VHL gene, results from a G to C substitution at nucleotide position 46. The glutamic acid at codon 16 is replaced by glutamine, an amino acid with highly similar properties. 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.76
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.053	T
Polyphen		0.95	P
Vest4		0.13
MutPred		0.20		Gain of helix (P = 0.132)
MVP		0.97
MPC		0.57
ClinPred		0.19	T
GERP RS		1.4
PromoterAI		-0.10	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.14
gMVP		0.48
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs1060503556; hg19: chr3-10183577;