3-10141921-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The variant NM_000551.3(VHL):c.74C>T (p.Pro25Leu) in VHL is a missense variant occurring prior to the second start site. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.005329 (6211/1141350 from European, Non-Finnish Population). This is higher than the ClinGen VHL VCEP threshold of >=0.000156 (0.0156%) threshold expected for VHL disease (BA1). In summary, this variant meets the criteria to be classified as Benign for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA020538/MONDO:0008667/078

Frequency

Genomes: 𝑓 0.0025 ( 2 hom., cov: 33)
Exomes 𝑓: 0.0047 ( 20 hom. )

Consequence

VHL
NM_000551.4 missense

Scores

1
3
14

Clinical Significance

Benign reviewed by expert panel P:1B:24O:1

Conservation

PhyloP100: -0.0370
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
VHLNM_000551.4 linkc.74C>T p.Pro25Leu missense_variant 1/3 ENST00000256474.3 NP_000542.1 P40337-1A0A024R2F2
VHLNM_001354723.2 linkc.74C>T p.Pro25Leu missense_variant 1/3 NP_001341652.1
VHLNM_198156.3 linkc.74C>T p.Pro25Leu missense_variant 1/2 NP_937799.1 P40337-2A0A0S2Z4K1
VHLNR_176335.1 linkn.144C>T non_coding_transcript_exon_variant 1/4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
VHLENST00000256474.3 linkc.74C>T p.Pro25Leu missense_variant 1/31 NM_000551.4 ENSP00000256474.3 P40337-1

Frequencies

GnomAD3 genomes
AF:
0.00252
AC:
383
AN:
152220
Hom.:
2
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000723
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000589
Gnomad ASJ
AF:
0.00663
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00145
Gnomad FIN
AF:
0.000565
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00447
Gnomad OTH
AF:
0.00191
GnomAD3 exomes
AF:
0.00303
AC:
439
AN:
144690
Hom.:
3
AF XY:
0.00294
AC XY:
226
AN XY:
76752
show subpopulations
Gnomad AFR exome
AF:
0.000512
Gnomad AMR exome
AF:
0.000753
Gnomad ASJ exome
AF:
0.0105
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00136
Gnomad FIN exome
AF:
0.000812
Gnomad NFE exome
AF:
0.00514
Gnomad OTH exome
AF:
0.00409
GnomAD4 exome
AF:
0.00471
AC:
6537
AN:
1387200
Hom.:
20
Cov.:
32
AF XY:
0.00460
AC XY:
3142
AN XY:
682572
show subpopulations
Gnomad4 AFR exome
AF:
0.000739
Gnomad4 AMR exome
AF:
0.000946
Gnomad4 ASJ exome
AF:
0.00799
Gnomad4 EAS exome
AF:
0.0000282
Gnomad4 SAS exome
AF:
0.00159
Gnomad4 FIN exome
AF:
0.000933
Gnomad4 NFE exome
AF:
0.00550
Gnomad4 OTH exome
AF:
0.00358
GnomAD4 genome
AF:
0.00251
AC:
383
AN:
152338
Hom.:
2
Cov.:
33
AF XY:
0.00217
AC XY:
162
AN XY:
74490
show subpopulations
Gnomad4 AFR
AF:
0.000721
Gnomad4 AMR
AF:
0.000588
Gnomad4 ASJ
AF:
0.00663
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00145
Gnomad4 FIN
AF:
0.000565
Gnomad4 NFE
AF:
0.00447
Gnomad4 OTH
AF:
0.00189
Alfa
AF:
0.00443
Hom.:
0
Bravo
AF:
0.00269
ESP6500AA
AF:
0.00129
AC:
5
ESP6500EA
AF:
0.00366
AC:
28
ExAC
AF:
0.00161
AC:
143
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Pathogenic:1Benign:24Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not specified Benign:9Other:1
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Dec 18, 2012- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJul 07, 2023The p.Pro25Leu variant in VHL is classified as likely benign because it has been identified in 0.66% (23/3470) of Ashkenazi Jewish chromosomes and 0.45% (304/68032) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was shown not to segregate with disease in 2 affected individuals from 2 families. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. ACMG/AMP Criteria applied: BS1, BS4, BP4. -
not provided, no classification providedreference populationITMISep 19, 2013- -
Benign, criteria provided, single submitterclinical testingGeneDxDec 11, 2013This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoApr 27, 2017- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesFeb 23, 2018- -
Likely benign, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
not provided Benign:7
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2024VHL: BS2 -
Likely benign, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenNov 03, 2021- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 13, 2023- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Likely benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsOct 05, 2015- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Likely benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Von Hippel-Lindau syndrome Benign:5
Benign, criteria provided, single submitterclinical testingGenomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of PhiladelphiaJul 09, 2015- -
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMar 23, 2018- -
Likely benign, no assertion criteria providedclinical testingClinical Genomics Labs, University Health NetworkJul 12, 2019- -
Benign, reviewed by expert panelcurationClinGen VHL Variant Curation Expert Panel, ClinGenJun 25, 2024The variant NM_000551.3(VHL):c.74C>T (p.Pro25Leu) in VHL is a missense variant occurring prior to the second start site. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.005329 (6211/1141350 from European, Non-Finnish Population). This is higher than the ClinGen VHL VCEP threshold of >=0.000156 (0.0156%) threshold expected for VHL disease (BA1). In summary, this variant meets the criteria to be classified as Benign for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 06, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submittercurationSema4, Sema4Jul 21, 2020- -
Benign, criteria provided, single submitterclinical testingAmbry GeneticsJul 09, 2015This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Maffucci syndrome Pathogenic:1
Likely pathogenic, flagged submissionresearchBaylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine-- -
Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.088
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
19
DANN
Uncertain
0.98
DEOGEN2
Benign
0.33
T;.
Eigen
Benign
-0.90
Eigen_PC
Benign
-0.92
FATHMM_MKL
Benign
0.37
N
LIST_S2
Uncertain
0.90
D;D
MetaRNN
Benign
0.0057
T;T
MetaSVM
Benign
-0.68
T
MutationAssessor
Benign
0.55
N;N
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-0.73
N;N
REVEL
Benign
0.15
Sift
Pathogenic
0.0
.;D
Sift4G
Benign
0.18
T;T
Polyphen
0.0
B;B
Vest4
0.17
MVP
0.92
MPC
0.83
ClinPred
0.076
T
GERP RS
2.5
Varity_R
0.11
gMVP
0.50

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.

Other links and lift over

dbSNP: rs35460768; hg19: chr3-10183605; COSMIC: COSV56547511; COSMIC: COSV56547511; API