Submissions for variant NM_000551.4(VHL):c.74C>T (p.Pro25Leu)

gnomAD frequency: 0.00261  dbSNP: rs35460768

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen VHL Variant Curation Expert Panel, ClinGen	RCV000119213	SCV005187294	benign	Von Hippel-Lindau syndrome	2024-06-25	reviewed by expert panel	curation	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).
Eurofins Ntd Llc (ga)	RCV000079211	SCV000111081	benign	not specified	2012-12-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082579	SCV000153955	benign	Chuvash polycythemia; Von Hippel-Lindau syndrome	2025-02-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000079211	SCV000169801	benign	not specified	2013-12-11	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.
Ambry Genetics	RCV000126300	SCV000212721	benign	Hereditary cancer-predisposing syndrome	2015-07-09	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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000119213	SCV000257721	benign	Von Hippel-Lindau syndrome	2015-07-09	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224298	SCV000281295	likely benign	not provided	2015-10-05	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
PreventionGenetics, part of Exact Sciences	RCV000079211	SCV000305277	benign	not specified	2018-02-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000119213	SCV000439634	benign	Von Hippel-Lindau syndrome	2018-03-06	criteria provided, single submitter	clinical testing	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.
Genetic Services Laboratory, University of Chicago	RCV000079211	SCV000597845	benign	not specified	2017-04-27	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224298	SCV000605561	benign	not provided	2024-08-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000224298	SCV000780755	likely benign	not provided	2025-04-01	criteria provided, single submitter	clinical testing	VHL: BS2
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000224298	SCV002011306	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000126300	SCV002534201	benign	Hereditary cancer-predisposing syndrome	2020-07-21	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000079211	SCV002552393	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000119213	SCV004360950	benign	Von Hippel-Lindau syndrome	2018-03-23	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000079211	SCV004847571	benign	not specified	2023-07-07	criteria provided, single submitter	clinical testing	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.
Breakthrough Genomics, Breakthrough Genomics	RCV000224298	SCV005264527	likely benign	not provided		criteria provided, single submitter	not provided
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000119213	SCV005880431	benign	Von Hippel-Lindau syndrome	2025-02-01	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005394340	SCV006054182	benign	Chuvash polycythemia; Pheochromocytoma; Von Hippel-Lindau syndrome; Nonpapillary renal cell carcinoma	2022-08-09	criteria provided, single submitter	clinical testing
ITMI	RCV000079211	SCV000086484	not provided	not specified	2013-09-19	no assertion provided	reference population
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000224298	SCV001739990	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000224298	SCV001807641	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000079211	SCV001929331	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genomics Labs, University Health Network	RCV000119213	SCV001950146	likely benign	Von Hippel-Lindau syndrome	2019-07-12	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000079211	SCV001957553	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000079211	SCV001966110	benign	not specified		no assertion criteria provided	clinical testing
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV002467563	SCV002764261	likely pathogenic	Maffucci syndrome		flagged submission	research