rs1553619456

Positions:

• chr3-10142149-T-A
• chr3-10142149-T-C

Variant summary

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

The NM_000551.4(VHL):​c.302T>A​(p.Leu101Gln) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L101G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.05

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 region_of_interest Involved in binding to CCT complex (size 55) in uniprot entity VHL_HUMAN there are 32 pathogenic changes around while only 1 benign (97%) in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 3-10142149-T-A is Pathogenic according to our data. Variant chr3-10142149-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1799025.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.302T>A	p.Leu101Gln	missense_variant	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.302T>A	p.Leu101Gln	missense_variant	1/3		NP_001341652.1
VHL	NM_198156.3	c.302T>A	p.Leu101Gln	missense_variant	1/2		NP_937799.1
VHL	NR_176335.1	n.372T>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.302T>A	p.Leu101Gln	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: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2022

The p.L101Q variant (also known as c.302T>A), located in coding exon 1 of the VHL gene, results from a T to A substitution at nucleotide position 302. The leucine at codon 101 is replaced by glutamine, an amino acid with dissimilar properties. Based on internal structural analysis, L101Q is disruptive to the local structure and is more disruptive that other nearly pathogenic variants in this region (Ambry internal data). Two other alterations at the same codon, p.L101P and p.L101R, have been detected in multiple patients with Von Hippel-Lindau disease (VHL) (Zbar, B et al. Hum Mutat. 1996;8(4):348-57; Rocha, JC et al. J Med Genet. 2003 Mar;40(3):e31; Taylor C et al. Int. J. Oncol., 2012 Oct;41:1229-40; Kim, HJ et al. Laryngoscope. 2013 Feb;123(2):477-83). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	0.80	D;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0020	.;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.99	D;D
Vest4		0.85
MutPred		0.86		Loss of glycosylation at P103 (P = 0.0211);Loss of glycosylation at P103 (P = 0.0211);
MVP		1.0
MPC		1.0
ClinPred		0.98	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
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: chr3-10183833; COSMIC: COSV56543987; COSMIC: COSV56543987;