3-10149810-C-T

Variant names:

• chr3-10149810-C-T
• rs1553620318
• NM_000551.4:c.487C>T

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.487C>T​(p.Leu163Phe) 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: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.47

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, 0.976
• PP5: Variant 3-10149810-C-T is Pathogenic according to our data. Variant chr3-10149810-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 480772.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.487C>T	p.Leu163Phe	missense_variant	Exon 3 of 3	ENST00000256474.3	NP_000542.1
VHL	NM_198156.3	c.364C>T	p.Leu122Phe	missense_variant	Exon 2 of 2		NP_937799.1
VHL	NM_001354723.2	c.*41C>T		3_prime_UTR_variant	Exon 3 of 3		NP_001341652.1
VHL	NR_176335.1	n.816C>T		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.487C>T	p.Leu163Phe	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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:1

Nov 25, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: VHL c.487C>T (p.Leu163Phe) 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. Five of five in-silico tools predict a damaging effect of the variant on protein function. At-least one additional variant that alters the same codon (c.488T>C, p.Leu162Pro) has been reported with a classification of Likely Pathogenic, supporting the critical relevance of this residue to VHL protein function. The variant was absent in 251440 control chromosomes. c.487C>T has been reported in the literature in individuals affected with Von Hippel-Lindau Syndrome (example, Tong_2006, Pandit_2016, Lomte_2018, Goldstein_2020, Internal data). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32671223, 29124493, 27539324, 17102088). ClinVar contains an entry for this variant (Variation ID: 480772). Based on the evidence outlined above, the variant was classified as pathogenic. -

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

May 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant disrupts the p.Leu163 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11986208, 19270817; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function. This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 163 of the VHL protein (p.Leu163Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 29124493, 32671223; Invitae). This variant is also known as 700C>T. ClinVar contains an entry for this variant (Variation ID: 480772). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 15, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L163F variant (also known as c.487C>T), located in coding exon 3 of the VHL gene, results from a C to T substitution at nucleotide position 487. The leucine at codon 163 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with a personal and/or family history of VHL-associated 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). Further, alterations at the same codon, p.L163P and p.L163R, have been reported in individuals with presumed sporadic Von Hippel-Lindau (VHL), as well as isolated pheochromocytoma (Cho HJ et al, J. Korean Med. Sci. 2009 Feb; 24(1):77-83; Sansó G et al, Am. J. Hypertens. 2004 Dec; 17(12 Pt 1):1107-11). Based on internal structural assessment, this alteration destabilizes the VHL elongin binding domain (Van Molle I et al. Chem. Biol., 2012 Oct;19:1300-12). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly 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	0.89
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Benign	2.0	M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.3	N;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0050	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.67
MutPred		0.87		Loss of catalytic residue at L163 (P = 0.004);.;
MVP		1.0
MPC		1.1
ClinPred		0.95	D
GERP RS		4.9
Varity_R		0.97
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1553620318; hg19: chr3-10191494; COSMIC: COSV104374385;