Submissions for variant NM_000551.4(VHL):c.463+8C>T

gnomAD frequency: 0.00050  dbSNP: rs5030834

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen VHL Variant Curation Expert Panel, ClinGen	RCV000123108	SCV005187298	benign	Von Hippel-Lindau syndrome	2024-06-25	reviewed by expert panel	curation	The variant NM_000551.4(VHL):c.463+8C>T is an intronic variant. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.001101 (1359/1179388 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). Therefore this variant meets the criterion for (BA1) and is 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).
GeneDx	RCV000115747	SCV000149656	likely benign	not specified	2017-11-01	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084968	SCV000166410	benign	Chuvash polycythemia; Von Hippel-Lindau syndrome	2025-02-03	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000210772	SCV000267099	likely benign	Hereditary cancer-predisposing syndrome	2016-02-05	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000115747	SCV000540656	likely benign	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Outside splice consensus; 2 pubs in HGMD describe 1 proband with no segs
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589592	SCV000697517	benign	not provided	2016-01-13	criteria provided, single submitter	clinical testing	Variant summary: Variant of interest is a substitution of a non-conserved nucleotide located at an intronic position not widely known to affect splicing. 5/5 in silico tools via Alamut predict no impact on normal splicing by the variant along with mutation taster predicting a neutral outcome. The variant was found in the European and African subcohorts of the ExAC project at an allele frequency of 0.076% and 0.048% respectively. These allele frequencies exceed the maximal expected allele frequency of a disease causing VHL variant (0.0028%) indicating the variant to be non-disease causing. It was also seen in patients with phaeochromocytoma, suspected VHL disease and with sporadic RCC, however without strong evidence for pathogenicity. Multiple clinical diagnostic laboratories classify variant as Likely Benign/Benign via ClinVar (without evidence to independently evaluate). Considering the high prevalence of the variant in the general population this variant is classified as benign.
PreventionGenetics, part of Exact Sciences	RCV000589592	SCV000805351	likely benign	not provided	2017-02-17	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000589592	SCV001153780	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	VHL: BP4
Illumina Laboratory Services, Illumina	RCV000123108	SCV001304545	uncertain significance	Von Hippel-Lindau syndrome	2018-08-08	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000589592	SCV002011310	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000115747	SCV002070985	likely benign	not specified	2021-08-06	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000210772	SCV002534176	likely benign	Hereditary cancer-predisposing syndrome	2021-02-21	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000115747	SCV002552404	benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000210772	SCV002636643	benign	Hereditary cancer-predisposing syndrome	2021-08-05	criteria provided, single submitter	clinical testing	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115747	SCV004221483	benign	not specified	2023-03-30	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population (http://gnomad.broadinstitute.org) is higher than would generally be expected for pathogenic variants in this gene. Computational tools yielded predictions that this variant is unlikely to have an effect on normal RNA splicing. This nucleotide position exhibits low evolutionary conservation.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000123108	SCV005921232	benign	Von Hippel-Lindau syndrome	2024-12-30	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000123108	SCV000264746	likely benign	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing
Counsyl	RCV000123108	SCV000785566	likely benign	Von Hippel-Lindau syndrome	2017-09-20	no assertion criteria provided	clinical testing	This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact [e-mail].
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000589592	SCV001741627	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000589592	SCV001808973	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000589592	SCV001930615	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genomics Labs, University Health Network	RCV000123108	SCV001950149	likely benign	Von Hippel-Lindau syndrome	2018-11-22	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000589592	SCV001956241	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000589592	SCV001968532	likely benign	not provided		no assertion criteria provided	clinical testing