NM_000551.4:c.620C>T

Variant names:

• chr3-10149943-C-T
• rs1060503549
• NM_000551.4:c.620C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000551.4(VHL):​c.620C>T​(p.Ala207Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A207K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 0.799
• Publications: 6 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp, G2P
• 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

ENSG00000287086 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 29 uncertain in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17545956).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	NM_000551.4	MANE Select	c.620C>T	p.Ala207Val	missense	Exon 3 of 3	NP_000542.1	A0A024R2F2
	VHL	NM_198156.3		c.497C>T	p.Ala166Val	missense	Exon 2 of 2	NP_937799.1	A0A0S2Z4K1
	VHL	NM_001354723.2		c.*174C>T		3_prime_UTR	Exon 3 of 3	NP_001341652.1	A0A8Q3WL21

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	ENST00000256474.3	TSL:1 MANE Select	c.620C>T	p.Ala207Val	missense	Exon 3 of 3	ENSP00000256474.3	P40337-1
	VHL	ENST00000345392.3	TSL:1	c.497C>T	p.Ala166Val	missense	Exon 2 of 2	ENSP00000344757.2	P40337-2
	VHL	ENST00000477538.2	TSL:1	n.1500C>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251200 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

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: 0.00000274 AC: 4 AN: 1461742 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727156

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000895 AC: 4 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111944

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	not provided (1)
-	1	-	Von Hippel-Lindau syndrome (1)
-	1	-	Von Hippel-Lindau syndrome;C0031511:Pheochromocytoma;C1837915:Chuvash polycythemia;CN074294:Nonpapillary renal cell carcinoma (1)
-	1	-	Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.30	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	0.0	N
PhyloP100		0.80
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.84	N
REVEL	Uncertain	0.52
Sift	Benign	0.064	T
Sift4G	Uncertain	0.049	D
Polyphen		0.0	B
Vest4		0.060
MutPred		0.68		Gain of catalytic residue at A207 (P = 0.0203)
MVP		0.89
MPC		0.33
ClinPred		0.033	T
GERP RS		-0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.52
gMVP		0.38
Mutation Taster		=85/15	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: rs1060503549; hg19: chr3-10191627;