ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.208G>A (p.Glu70Lys) (rs5030802)

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Total submissions: 7
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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 2016-02-03 criteria provided, single submitter clinical testing Variant summary: The c.208G>A variant affects a conserved nucleotide, resulting in amino acid change from Glu to Lys. 4/4 in-silico tools predict benign outcome for this variant (SNPs&GO not captured due to low reliability index); however, these in silico predictions have not been verified with functional studies. This variant is found in 1/67270 control chromosomes at a frequency of 0.0000149, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0000208). This variant has been found in at least 10 unrelated VHL patients and is reported as the most common pathogenic variant in Korean patients (Hwang_2014). In addition, one clinical laboratory classified this variant as pathogenic. Taken together, this 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 likely pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2020-04-01 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 70 of the VHL protein (p.Glu70Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs5030802, ExAC 0.008%). This variant has been observed in individual(s) with clinical features of von Hippel-Lindau syndrome (PMID: 9829912, 25715769, 25078357, 17661816, 25562111, 27439424, 19408298, 19270817). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43598). This variant has been reported to have conflicting or insufficient data to determine the effect on VHL protein function (PMID: 15611064). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare 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

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