Submissions for variant NM_000551.4(VHL):c.242C>T (p.Pro81Leu)

gnomAD frequency: 0.00001  dbSNP: rs193922608

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030582	SCV000053258	likely pathogenic	Von Hippel-Lindau syndrome	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Likely pathogenic.
Ambry Genetics	RCV000129974	SCV000184798	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-01-09	criteria provided, single submitter	clinical testing	The p.P81L variant (also known as c.242C>T), located in coding exon 1 of the VHL gene, results from a C to T substitution at nucleotide position 242. The proline at codon 81 is replaced by leucine, an amino acid with very few similar properties. This alteration has been reported in multiple individuals with diagnoses consistent with of von Hippel-Lindau syndrome (VHL), but not clearly meeting clinical diagnostic criteria; including an individual with a right carotid body paraganglioma (Piccini V et al. Endocr Relat Cancer. 2012 Apr 10;19(2):149-55), a patient with a left para-adrenal paraganglioma (Castellano M et al. Ann N Y Acad Sci. 2006 Aug;1073:156-65), an individual diagnosed with VHL type 2C (Formenti F et al. FASEB J. 2011 Jun;25(6):2001-11), and an individual with pheochromocytoma at age 16 (Kim JH et al. Clin Genet, 2014 Nov;86:482-6). Further, another alteration at this codon, p.P81S (c.241C>T) has been described both as a low-penetrance mutation in VHL type 1 families (Gläsker S et al. J. Neurol. Neurosurg. Psychiatr. 1999 Dec;67:758-62; Glavac D et al. Hum. Genet. 1996 Sep;98:271-80; Hes FJ et al. J. Med. Genet. 2000 Dec;37:939-43; Kondo K et al. Hum. Mol. Genet. 1995 Dec;4:2233-7; Yoshida M et al. Jpn J Cancer Res. 2000 Feb;90:204-212; Zbar B et al. Hum. Mutat. 1996;8:348-57; Alosi D et al. Curr. Genomics. 2017 Feb;18:93-103) and as a nonpathogenic alteration (Erlic Z et al. J Clin Endocrinol Metab. 2010 Jan;95:308-13). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic; however, individuals may not present with classic von Hippel-Lindau syndrome. Clinical correlation is advised.
Invitae	RCV001034657	SCV000553390	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 81 of the VHL protein (p.Pro81Leu). This variant is present in population databases (rs193922608, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of von Hippel-Lindau disease (type 2C: pheochromocytoma and paraganglioma) (PMID: 17102082, 21389259, 22241717, 24134185, 27730413; Invitae). ClinVar contains an entry for this variant (Variation ID: 36899). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001547784	SCV001767572	likely pathogenic	not provided	2022-04-13	criteria provided, single submitter	clinical testing	Observed in individuals with isolated pheochromocytoma and/or paraganglioma and no other features of von Hippel Lindau syndrome (Castellano 2006, Piccini 2012, Kim 2014, ClinVar SCV000553390.2); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.455C>T, p.Pro152Leu, and p.Pro122Leu; This variant is associated with the following publications: (PMID: 24446253, 27730413, 29946849, 22241717, 17102082, 24134185, 21389259, 31589614)
CeGaT Center for Human Genetics Tuebingen	RCV001547784	SCV002496778	likely pathogenic	not provided	2022-02-01	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000030582	SCV004183372	likely pathogenic	Von Hippel-Lindau syndrome	2021-03-31	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3, PS4, PM2, PP3
Baylor Genetics	RCV003460493	SCV004208788	likely pathogenic	Chuvash polycythemia	2023-04-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000030582	SCV004841640	likely pathogenic	Von Hippel-Lindau syndrome	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 81 of the VHL protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with VHL-associated tumor or have a VHL diagnosis (PMID: 17102082, 21389259, 22241717, 24134185, 33219105). This variant has been identified in 1/229958 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000030582	SCV000264681	likely pathogenic	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing
Clinical Genomics Labs, University Health Network	RCV000030582	SCV002601728	likely pathogenic	Von Hippel-Lindau syndrome	2022-02-21	no assertion criteria provided	clinical testing