Submissions for variant NM_000551.4(VHL):c.208G>A (p.Glu70Lys)

dbSNP: rs5030802

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492137	SCV000580979	likely pathogenic	Hereditary cancer-predisposing syndrome	2017-10-09	criteria provided, single submitter	clinical testing	The p.E70K variant (also known as c.208G>A), located in coding exon 1 of the VHL gene, results from a G to A substitution at nucleotide position 208. The glutamic acid at codon 70 is replaced by lysine, an amino acid with similar properties. Some studies have proposed this alteration as a Korean hotspot mutation that causes a phenotype consistent with VHL type 1 (Hwang S et al. J. Hum. Genet. 2014 Sep;59(9):488-93; Lee JS et al. BMC Med. Genet. 2016 Jul;17(1):48). It has been identified in many unrelated Korean families with histories of central nervous system and retinal hemangioblastomas (Olschwang S et al. Hum Mut. 1998;12:424; Hes FJ et al. Clin Genet. 2007;72:122; Cho HJ et al. J Korean Med Sci. 2009 Feb;24(1):77-83; Hwang S et al. J. Hum. Genet. 2014 Sep;59(9):488-93; Lee JS et al. BMC Med. Genet. 2016 Jul;17(1):48). It was also seen in a 74-year-old Korean patient with renal clear cell carcinoma and central nervous system hemangioblastomas, as well as a colorectal adenocarcinoma. This patient's two brothers, also presenting with renal cell carcinoma, were positive for the p.E70K alteration (Heo SJ et al. Cancer Res Treat. 2016 Jan;48(1):409-14). In addition, a functional study demonstrated that this alteration led to a modest reduction (20%) in the ability of the VHL protein to bind with the alpha subunit of the hypoxia-inducible transcription factor (HIF) and failure to degrade HIF-2 alpha (Miller F et al. J Biol Chemistry. 2005;280(9):7986). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036540	SCV000697485	pathogenic	Von Hippel-Lindau syndrome	2023-04-10	criteria provided, single submitter	clinical testing	Variant summary: VHL c.208G>A (p.Glu70Lys) results in a conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, beta/alpha domain (IPR022772) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-06 in 229204 control chromosomes (gnomAD). c.208G>A has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome (examples: Hes_2007 and Hwang_2014). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000036540	SCV000782417	pathogenic	Von Hippel-Lindau syndrome	2016-11-01	criteria provided, single submitter	clinical testing
CIViC knowledgebase, Washington University School of Medicine	RCV000036540	SCV001192829	likely pathogenic	Von Hippel-Lindau syndrome		criteria provided, single submitter	curation	VHL E70K (c.208G>A) is Likely Pathogenic. E70K missense variant occurs at a very low allele frequency in the general population (0.00001489 allele frequency in ExAC, 4.365e-6 allele frequency in gnomAD) and was previously identified in several unrelated individuals with VHL disease symptoms (see evidence statements). PM1 (6860); PM2 (per above); PP1 (5805); PP4 (5805;6742).
Invitae	RCV001379599	SCV001577426	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 70 of the VHL protein (p.Glu70Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with clinical features of von Hippel-Lindau syndrome (VHL) (PMID: 9829912, 17661816, 19270817, 19408298, 25078357, 25562111, 25715769, 27439424; Invitae). It is commonly reported in individuals of Korean ancestry (PMID: 25078357). ClinVar contains an entry for this variant (Variation ID: 43598). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on VHL function (PMID: 15611064). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000036540	SCV004185990	likely pathogenic	Von Hippel-Lindau syndrome	2023-11-01	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 15611064]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 25078357, 27439424, 36384467, 31087189].
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036540	SCV000060195	pathogenic	Von Hippel-Lindau syndrome	2007-04-11	no assertion criteria provided	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000036540	SCV000264671	pathogenic	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing