chr3-10142041-C-T

Variant names:

• chr3-10142041-C-T
• rs5030826
• NM_000551.4:c.194C>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.194C>T​(p.Ser65Leu) 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. S65P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 4.92

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 18 ACMG points.

• PM1: In a chain von Hippel-Lindau disease tumor suppressor (size 212) in uniprot entity VHL_HUMAN there are 96 pathogenic changes around while only 8 benign (92%) 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 chr3-10142040-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 3-10142041-C-T is Pathogenic according to our data. Variant chr3-10142041-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 182975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10142041-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.194C>T	p.Ser65Leu	missense_variant	Exon 1 of 3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.194C>T	p.Ser65Leu	missense_variant	Exon 1 of 3		NP_001341652.1
VHL	NM_198156.3	c.194C>T	p.Ser65Leu	missense_variant	Exon 1 of 2		NP_937799.1
VHL	NR_176335.1	n.264C>T		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.194C>T	p.Ser65Leu	missense_variant	Exon 1 of 3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Nov 14, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 65 of the VHL protein (p.Ser65Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of von Hippel-Lindau syndrome (PMID: 7987306, 10567493, 12114495, 22799452). This variant is also known as Ser136Leu. ClinVar contains an entry for this variant (Variation ID: 182975). 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. Experimental studies have shown that this missense change affects VHL function (PMID: 15611064). This variant disrupts the p.Ser65 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7728151, 7987306, 22799452, 23384228). 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. -

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GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 06-17-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Aug 23, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S65L pathogenic mutation (also known as c.194C>T), located in coding exon 1 of the VHL gene, results from a C to T substitution at nucleotide position 194. The serine at codon 65 is replaced by leucine, an amino acid with dissimilar properties. This variant has been observed in multiple individuals with a personal and/or family history that is consistent with von Hippel-Lindau (VHL) syndrome (Ambry internal data; Cybulski C et al. J Med Genet, 2002 Jul;39:E38; Skalova A et al. Pathol Res Pract, 2008 Apr;204:599-606; Dandanell M et al. BMC Med Genet, 2012 Jul;13:54; Hong B et al. Front Genet, 2019 Sep;10:867; Ayub N et al. Endocrinol Diabetes Metab Case Rep, 2022 Mar;2022). In an in vitro assay, a mutant S65L VHL protein demonstrated that while the mutant protein can still form the correct E3 protein complex, the complex completely lost the ability to bind and promote degradation of hypoxia-inducible transcription factor (Miller, F. J Biol Chem. 2005 Mar 4;280(9):7985-96). 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 supporting evidence, this variant is interpreted as a disease-causing mutation. -

Pancreatic cysts;C0730303:Retinal capillary hemangioma;C1332900:Cerebellar hemangioblastoma;C4024223:Spinal hemangioblastoma Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.78
Sift	Benign	0.19	.;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.81	P;P
Vest4		0.96
MutPred		0.82		Gain of glycosylation at S68 (P = 0.0297);Gain of glycosylation at S68 (P = 0.0297);
MVP		1.0
MPC		1.0
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.96
gMVP		1.0

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: rs5030826; hg19: chr3-10183725; COSMIC: COSV56543026; COSMIC: COSV56543026;