Genetic Variant VHL:p.Gln195Lys (chr3-10149906-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000551.4(VHL):c.583C>A(p.Gln195Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q195R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

VHL
NM_000551.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.273

Publications

0 publications found

Variant links:

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

VHL links:

ENSG00000287086 (HGNC:):

ENSG00000287086 links:

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ACMG classification

Classification was made for transcript

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

PM1

In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 20 uncertain in NM_000551.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15406427).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VHL	NM_000551.4	MANE Select	c.583C>A	p.Gln195Lys	missense	Exon 3 of 3	NP_000542.1	A0A024R2F2
VHL	NM_198156.3		c.460C>A	p.Gln154Lys	missense	Exon 2 of 2	NP_937799.1	A0A0S2Z4K1
VHL	NM_001354723.2		c.*137C>A		3_prime_UTR	Exon 3 of 3	NP_001341652.1	A0A8Q3WL21

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VHL	ENST00000256474.3	TSL:1 MANE Select	c.583C>A	p.Gln195Lys	missense	Exon 3 of 3	ENSP00000256474.3	P40337-1
VHL	ENST00000345392.3	TSL:1	c.460C>A	p.Gln154Lys	missense	Exon 2 of 2	ENSP00000344757.2	P40337-2
VHL	ENST00000477538.2	TSL:1	n.1463C>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

8.0

(source)

DANN

Benign

0.70

DEOGEN2

Uncertain

0.65

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.53

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.15

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.20

PhyloP100

-0.27

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.89

REVEL

Uncertain

0.49

Sift

Benign

0.42

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.080

MutPred

0.43

Gain of ubiquitination at Q195 (P = 0.0121)

MVP

0.99

MPC

0.41

ClinPred

0.024

GERP RS

0.47

Varity_R

0.76

gMVP

0.69

Mutation Taster

=76/24

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over