Submissions for variant NM_000551.4(VHL):c.241C>T (p.Pro81Ser)

gnomAD frequency: 0.00039  dbSNP: rs104893829

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen VHL Variant Curation Expert Panel, ClinGen	RCV000002321	SCV005187310	benign	Von Hippel-Lindau syndrome	2024-06-25	reviewed by expert panel	curation	The variant NM_000551.4(VHL):c.241C>T (p.Pro81Ser) is a missense variant in the first exon of the VHL gene. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.0004281 (543/1179690 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	RCV000656990	SCV000149653	likely benign	not provided	2021-12-22	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
CSER _CC_NCGL, University of Washington	RCV000002321	SCV000190677	likely benign	Von Hippel-Lindau syndrome	2016-10-01	criteria provided, single submitter	research	Found in patient having exome sequencing for an unrelated indication. No known history of von Hippel-Lindau syndrome. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Ambry Genetics	RCV000115744	SCV000212872	likely benign	Hereditary cancer-predisposing syndrome	2021-03-22	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080004	SCV000254650	benign	Chuvash polycythemia; Von Hippel-Lindau syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000213077	SCV000540657	uncertain significance	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: Several reports describe as LB/non-pathogenic; ExAC: 0.04% (19/53684) European chromosomes
PreventionGenetics, part of Exact Sciences	RCV000656990	SCV000805331	likely benign	not provided	2017-10-02	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000002321	SCV000890934	uncertain significance	Von Hippel-Lindau syndrome	2023-07-11	criteria provided, single submitter	clinical testing	The VHL c.241C>T (p.Pro81Ser) missense change has a maximum subpopulation frequency of 0.044% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The variant is located in a mutational hotspot (COSMIC database). The in silico tool REVEL predicts a deleterious effect on protein function, and functional studies have shown mixed effects. Some functional studies have concluded that the variant behaves similar to the wild-type (Knauth 2009), whereas others suggest this variant may lead to reduced DNA damage response and resistance to ionizing radiation induced apoptosis (Li 2002, Desimone 2013). The Pro81Ser change has been reported in several individuals and families with Von Hippel Lindau-related cancers (Glavac 1996, Stolle 1998, Glasker 1999, Hes 2000, Weirich 2002, Erlic 2010, Haitz 2015, Alosi 2017). The Pro81Ser variant did not segregate with disease in a family with Von Hippel Lindau (Erlic 2009). In another family with several affected individuals, the variant was found to co-segregate in cis with another missense change in VHL (Weirich 2002). Since supporting evidence is conflicting, the clinical significance of this alteration remains unclear. It has therefore been classified as of uncertain significance.
Gharavi Laboratory, Columbia University	RCV000656990	SCV000920742	likely benign	not provided	2018-09-16	criteria provided, single submitter	research
Mendelics	RCV000002321	SCV001136311	uncertain significance	Von Hippel-Lindau syndrome	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000656990	SCV001153778	likely benign	not provided	2022-11-01	criteria provided, single submitter	clinical testing	VHL: PM1, PP3, BP2, BS4
Illumina Laboratory Services, Illumina	RCV000002321	SCV001311112	uncertain significance	Von Hippel-Lindau syndrome	2017-04-27	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.
Clinical Genomics Labs, University Health Network	RCV000002321	SCV001950150	uncertain significance	Von Hippel-Lindau syndrome	2020-09-08	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000656990	SCV002011313	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000213077	SCV002071720	uncertain significance	not specified	2020-03-19	criteria provided, single submitter	clinical testing	DNA sequence analysis of the VHL gene demonstrated a sequence change, c.241C>T, in exon 1 that results in an amino acid change, p.Pro81Ser. This sequence change has been described in the gnomAD database with a frequency of 0.04% in the European sub-population (dbSNP rs104893829). The p.Pro81Ser change has been reported in individuals with Von-Hippel Lindau-related cancers (PMIDs: 28503092, 19906784, 11106358, 9829911, 12414898, 8634692; Glavac 1996, Glasker 1999, Haitz 2015). This sequence change has been identified in two families that also had a likely pathogenic VHL variant in cis with this sequence change (PMIDs: 19906784, 12414898), and one family with a large deletion of the entire VHL gene in trans with this sequence change, in which the p.Pro81Ser change did not segregate with disease (PMID: 19906784). The p.Pro81Ser change has also been identified in three unrelated individuals with hemangioblastoma or renal cell carcinoma (Haitz 2015; PMID: 28503092, 11106358). Relatives of these individuals who carried the sequence change were not affected. Functional studies have suggested both normal protein activity (PMID: 19228690), and lack of ubiquitination, reduced DNA damage response, and resistance to ionizing radiation-induced apoptosis (Li 2002; PMID: 23990666) in the presence of this sequence change. The p.Pro81Ser change affects a highly conserved amino acid residue located in a domain of the VHL protein that is known to be functional. The p.Pro81Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Pro81Ser change remains unknown at this time.
Sema4, Sema4	RCV000115744	SCV002534150	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-25	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000213077	SCV002552399	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003225718	SCV003807914	uncertain significance	Chuvash polycythemia	2022-07-06	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting
Genetics and Molecular Pathology, SA Pathology	RCV000002321	SCV004175351	uncertain significance	Von Hippel-Lindau syndrome	2022-08-29	criteria provided, single submitter	clinical testing	The VHL c.241C>T variant is a single nucleotide change in exon 1/3 of the VHL gene, which is predicted to change the amino acid proline at position 81 in the protein to serine. This variant is situated at the alpha-beta domain interface (PM1). The population frequency is higher than expected for a disease-causing VHL variant (gnomAD 0.035%, 53/152206) (PM2 Not Met). This variant has been reported in several families and individuals with VHL-related syndromes, including RCC, hemangioblastoma, and paraganglioma (PMID: 28503092, 8707293, 9829911, 10567493, 11106358) (PS4). Erlic et al. (PMID: 19906784) reported an affected individual who had inherited this variant from his unaffected father, but who also had an in trans, de novo deletion of the entire VHL gene (BP2). Alosi et al. (PMID: 28503092) reported a kindred with 5 carriers of the variant and only one family member was affected with early onset renal clear cell cancer, suggesting that suggesting that the variant does not segregate with disease (BS4) or it may be a variant of variable penetrance. In silico tools suggest the impact of the variant on protein function is inconclusive. Functional studies have shown activity close to wildtype (PMID: 19228690), or a slight reduction to target protein binding with minimal impact to the protein complex functionality, except when in conjunction with another VHL variant (PMID: 22234250). The variant has been reported in dbSNP (rs104893829) and HGMD (CM951274). The variant has been reported with conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID:2233).
Mayo Clinic Laboratories, Mayo Clinic	RCV000656990	SCV004226048	uncertain significance	not provided	2023-02-06	criteria provided, single submitter	clinical testing	BS1, BP5
All of Us Research Program, National Institutes of Health	RCV000002321	SCV004841639	likely benign	Von Hippel-Lindau syndrome	2024-02-05	criteria provided, single submitter	clinical testing
OMIM	RCV000002321	SCV000022479	pathogenic	Von Hippel-Lindau syndrome	2002-11-01	no assertion criteria provided	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000002321	SCV000053257	likely benign	Von Hippel-Lindau syndrome	2015-10-02	no assertion criteria provided	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000002321	SCV000264680	uncertain significance	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing
Database of Curated Mutations (DoCM)	RCV000418681	SCV000505320	likely pathogenic	Neoplasm	2015-07-14	no assertion criteria provided	literature only
Molecular Oncology - Human Genetics Lab, University of Sao Paulo	RCV001843451	SCV002103110	uncertain significance	Hepatoblastoma		no assertion criteria provided	research
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV002467489	SCV002764243	likely pathogenic	Enchondromatosis		flagged submission	research