rs5030809

Positions:

• chr3-10142139-T-A
• chr3-10142139-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The ENST00000256474.3(VHL):​c.292T>A​(p.Tyr98Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y98H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL ENST00000256474.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.03

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 12 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 14 uncertain in ENST00000256474.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-10142139-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 2223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 3-10142139-T-A is Pathogenic according to our data. Variant chr3-10142139-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 2627292.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.292T>A	p.Tyr98Asn	missense_variant	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.292T>A	p.Tyr98Asn	missense_variant	1/3		NP_001341652.1
VHL	NM_198156.3	c.292T>A	p.Tyr98Asn	missense_variant	1/2		NP_937799.1
VHL	NR_176335.1	n.362T>A		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.292T>A	p.Tyr98Asn	missense_variant	1/3	1	NM_000551.4	ENSP00000256474	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 21, 2023

Variant summary: VHL c.292T>A (p.Tyr98Asn) results in a non-conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, beta/alpha domain (IPR022772) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 223372 control chromosomes (gnomAD). c.292T>A has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome (examples: Liu_2018, Krzystolik_2016). Other variants affecting the same residue (p.Tyr98His, p.Tyr98Cys) have been classifed pathogenic internally and in ClinVar (CV IDs: 2223, 223176). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 29595810, 26308528). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.99	D;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	0.76	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.1	D;D
REVEL	Pathogenic	0.95
Sift	Benign	0.19	.;T
Sift4G	Pathogenic	0.0	D;T
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.78		Loss of glycosylation at P103 (P = 0.0211);Loss of glycosylation at P103 (P = 0.0211);
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.94
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-10183823; COSMIC: COSV56553058; COSMIC: COSV56553058;