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
Consequence
NM_000551.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
VHL | NM_000551.4 | c.74C>T | p.Pro25Leu | missense_variant | 1/3 | ENST00000256474.3 | NP_000542.1 | |
VHL | NM_001354723.2 | c.74C>T | p.Pro25Leu | missense_variant | 1/3 | NP_001341652.1 | ||
VHL | NM_198156.3 | c.74C>T | p.Pro25Leu | missense_variant | 1/2 | NP_937799.1 | ||
VHL | NR_176335.1 | n.144C>T | non_coding_transcript_exon_variant | 1/4 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00252 AC: 383AN: 152220Hom.: 2 Cov.: 33
GnomAD3 exomes AF: 0.00303 AC: 439AN: 144690Hom.: 3 AF XY: 0.00294 AC XY: 226AN XY: 76752
GnomAD4 exome AF: 0.00471 AC: 6537AN: 1387200Hom.: 20 Cov.: 32 AF XY: 0.00460 AC XY: 3142AN XY: 682572
GnomAD4 genome AF: 0.00251 AC: 383AN: 152338Hom.: 2 Cov.: 33 AF XY: 0.00217 AC XY: 162AN XY: 74490
ClinVar
Submissions by phenotype
not specified Benign:9Other:1
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 18, 2012 | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 07, 2023 | The 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 provided | reference population | ITMI | Sep 19, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 11, 2013 | This 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 submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 27, 2017 | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 23, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not provided Benign:7
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | VHL: BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 13, 2023 | - - |
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Oct 05, 2015 | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Von Hippel-Lindau syndrome Benign:5
Benign, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Jul 09, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 23, 2018 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genomics Labs, University Health Network | Jul 12, 2019 | - - |
Benign, reviewed by expert panel | curation | ClinGen VHL Variant Curation Expert Panel, ClinGen | Jun 25, 2024 | 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). - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 2018 | This 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 submitter | curation | Sema4, Sema4 | Jul 21, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 09, 2015 | This 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 submission | research | Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine | - | - - |
Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at