3-10142103-C-T

Position:

chr3-10142103-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000256474.3(VHL):c.256C>T(p.Pro86Ser) 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. P86L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

VHL
ENST00000256474.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 4.84

Variant links:

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]

VHL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 13 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 chr3-10142104-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 182977.Status of the report is reviewed_by_expert_panel, 3 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 3-10142103-C-T is Pathogenic according to our data. Variant chr3-10142103-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 178692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10142103-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VHL	NM_000551.4 linkuse as main transcript	c.256C>T	p.Pro86Ser	missense_variant	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2 linkuse as main transcript	c.256C>T	p.Pro86Ser	missense_variant	1/3		NP_001341652.1
VHL	NM_198156.3 linkuse as main transcript	c.256C>T	p.Pro86Ser	missense_variant	1/2		NP_937799.1
VHL	NR_176335.1 linkuse as main transcript	n.326C>T		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3 linkuse as main transcript	c.256C>T	p.Pro86Ser	missense_variant	1/3	1	NM_000551.4	ENSP00000256474	P1	P40337-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1451274

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722338

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 29, 2016	Variant summary: This c.256C>T variant affects a conserved nucleotide, resulting in amino acid change from Pro to Ser in HIFalfa domain of VHL protein. 5/5 in-silico tools predict this variant to be damaging. The variant is absent from the large, broad ExAC control population. In literature, this variant has been reported multiple independent patients with Von Hippel-Lindau disease or related cancers, and has been shown to segregate with disease in at least one family. Other missense changes at this codon are also reported in association VHL disease, namely p.P86R, p.P86L and p.P86A, suggesting that this codon is likely to be a mutational hot-spot. One clinical lab (via ClinVar) and one reputable database classify this variant as pathogenic/likley pathogenic. Taken together, this variant has been classified as a Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 19, 2013	The Pro86Ser variant in VHL has been reported in 12 individuals with clinical fe atures of Von Hippel-Lindau syndrome, was absent from 276 control chromosomes, a nd segregated with disease in four affected family members across three families (Whaley 1994, Kondo 1995, Olschwang 1998, Dollfus 2002, Elii 2006, Ong 2007, Co rcos 2008, Ciotti 2009, Wu 2012). Computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for o r against an impact to the protein, however, proline (Pro) at position 86 is hig hly conserved across evolutionarily distant species, suggesting that a change to this position may not be tolerated. In addition, other variants at this positio n (Pro86Ala, Pro86Leu, Pro86Arg, and Pro86His) have been identified in patients with the clinical features of Von Hippel-Lindau syndrome (HGMD database, UMD dat abase). In summary, this variant is likely to be pathogenic, though additional s tudies are required to fully establish its clinical significance. -
Pathogenic, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 26, 2016	- -

Chuvash polycythemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Dec 17, 2024

- -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 22, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro86 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7728151, 9829911, 11257211, 17024664, 19408298). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 178692). This variant is also known as 469C>T, Pro157Ser. This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 8634692, 9829912, 19464396, 27057652, 27527340). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 86 of the VHL protein (p.Pro86Ser). -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 03, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.469C>T, p.P157S, p.P127S; This variant is associated with the following publications: (PMID: 25562111, 7977367, 23660872, 18836774, 8956040, 9829912, 15300849, 8634692, 16952288, 27057652, 22357542, 20151405, 17024664, 10761708, 16506495, 19464396, 19215943, 18580449, 27527340, 33774214, 34926252, Al-Hadlaq[article]2022) -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 06, 2023

The p.P86S pathogenic mutation (also known as c.256C>T), located in coding exon 1 of the VHL gene, results from a C to T substitution at nucleotide position 256. The proline at codon 86 is replaced by serine, an amino acid with similar properties. This mutation has been detected in multiple individuals meeting clinical criteria for Von Hippel-Lindau (VHL) disease with symptoms including retinal angiomas, cerebellar hemangioblastomas, pheochromocytomas, renal cell carcinoma, and pancreatic cysts and tumors (Kondo K et. al. Hum. Mol. Genet. 1995 Dec;4:2233-7; Ong KR, et al. Hum. Mutat. 2007 Feb;28:143-9; Whaley JM et al. Am. J. Hum. Genet. 1994 Dec;55:1092-102; Ciotti P et al. Eur J Med Genet. 2009 May;52:311-4; Dollfus H et al. Invest. Ophthalmol. Vis. Sci. 2002 Sep;43:3067-74; Elli L et al. Am. J. Gastroenterol. 2006 Nov;101:2655-8; Wu P et al. J. Hum. Genet. 2012 Apr;57:238-43; Rothberg PG et al. Mol. Diagn. 2001 Mar;6:49-54; Park TY et al. Scand. J. Gastroenterol. 2015 Mar;50:360-7; Olschwang S et al. Hum. Mutat. 1998;12:424-30; Gallou C et al. Hum. Mutat. 2004 Sep;24:215-24; Corcos O et al. Pancreas. 2008 Jul;37:85-93. Several other alterations at the same codon (p.P86A, p.P86L, and p.P86R) have been reported in individuals with VHL (Nordstrom-O'Brien M et al. Hum. Mutat. 2010 May;31:521-37). In addition, based on both internal structural analysis and published structural analysis, this alteration is anticipated to result in a significant decrease in structural stability (Van Molle I et al. Chem. Biol. 2012 Oct;19:1300-12; Yuan P et al. Cancer Biol. Ther. 2016 Jun;17:599-603). Of note, this mutation is also designated as p.P157S (c.469C>T) in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;.

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

D;D

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.2

M;M

MutationTaster

Benign

0.99

D;D

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-4.3

D;D

REVEL

Pathogenic

0.88

Sift

Benign

0.14

.;T

Sift4G

Uncertain

0.032

D;D

Polyphen

1.0

D;D

Vest4

0.87

MutPred

0.95

Gain of MoRF binding (P = 0.0471);Gain of MoRF binding (P = 0.0471);

MVP

1.0

MPC

1.1

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over