rs28940297

Variant names:

• chr3-10149811-T-C
• rs28940297
• NM_000551.4:c.488T>C

Your query was ambiguous. Multiple possible variants found:

• chr3-10149811-T-C
• chr3-10149811-T-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000551.4(VHL):​c.488T>C​(p.Leu163Pro) 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. L163R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.26

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]

ENSG00000287086 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a helix (size 11) in uniprot entity VHL_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) 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 chr3-10149811-T-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 3-10149811-T-C is Pathogenic according to our data. Variant chr3-10149811-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.488T>C	p.Leu163Pro	missense_variant	Exon 3 of 3	ENST00000256474.3	NP_000542.1
VHL	NM_198156.3	c.365T>C	p.Leu122Pro	missense_variant	Exon 2 of 2		NP_937799.1
VHL	NM_001354723.2	c.*42T>C		3_prime_UTR_variant	Exon 3 of 3		NP_001341652.1
VHL	NR_176335.1	n.817T>C		non_coding_transcript_exon_variant	Exon 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.488T>C	p.Leu163Pro	missense_variant	Exon 3 of 3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

RENAL CELL CARCINOMA WITH PARANEOPLASTIC ERYTHROCYTOSIS Pathogenic:1

May 15, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Von Hippel-Lindau syndrome Pathogenic:1

Mar 05, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 11986208]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 25078357, 29595810]. -

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

Aug 23, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Leu163 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 29124493, 15607616), which suggests that this may be a clinically significant amino acid residue. This variant has been reported to affect VHL protein function (PMID: 11986208). This variant has been observed in several individuals affected with Von Hippel-Lindau syndrome (PMID: 19270817, Invitae). ClinVar contains an entry for this variant (Variation ID: 2231). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 163 of the VHL protein (p.Leu163Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jun 08, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L163P variant (also known as c.488T>C), located in coding exon 3 of the VHL gene, results from a T to C substitution at nucleotide position 488. The leucine at codon 163 is replaced by proline, an amino acid with similar properties. This alteration has been observed in at least two individuals with a personal and/or family history that is consistent with VHL-related disease (Cho HJ et al. J Korean Med Sci, 2009 Feb;24:77-83; Ambry internal data). Another alteration at the same codon, p.L163F (c.487>T), has been detected in multiple individuals with a personal and/or family history of VHL-related disease (Tong AL et al. Ann. N. Y. Acad. Sci., 2006 Aug;1073:203-7; Pandit R et al. Eur. J. Endocrinol., 2016 12;175:X3; Lomte N et al. Fam Cancer, 2018 Jul;17:441-449; Goldstein M et al. AACE Clin Case Rep, 2020 May;6:e193-e196; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis.This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.86	D;T
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.010	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.96		Loss of helix (P = 0.0138);.;
MVP		1.0
MPC		1.4
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.99
gMVP		0.98

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

LitVar

Other links and lift over

dbSNP: rs28940297; hg19: chr3-10191495; COSMIC: COSV56546736;