ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.481C>T (p.Arg161Ter) (rs5030818)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000002301 SCV000053265 pathogenic Von Hippel-Lindau syndrome 2019-07-22 criteria provided, single submitter clinical testing Variant summary: VHL c.481C>T (p.Arg161X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251440 control chromosomes. c.481C>T has been extensively reported in the literature spanning over two decades to co-segregate with disease among multiple affected individuals from families with Von Hippel-Lindau Syndrome (example, Loeb_1994, Zbar_1996, Maher_1996, Li_1998, Cybulski_2002, Ruiz-Llorente_2004, Gallou_2004). These data indicate that the variant is very likely to be associated with disease. No experimental evidence demonstrating an impact on protein function was ascertained during this review. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV000161091 SCV000211826 pathogenic not provided 2019-02-04 criteria provided, single submitter clinical testing Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 53 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson 2014); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 21362373, 26514359, 23070752, 9829911, 12114495, 10408776, 21972040, 8956040, 25867206, 27527340, 7987306, 25720320, 24581539, 18446368, 9829912, 19574279, 11409863, 19996202, 28630796, 14987375, 9681856, 17661816, 11309459, 20064270, 16572651, 28849724, 7987327, 28469506, 20233476)
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000161091 SCV000228904 pathogenic not provided 2014-05-28 criteria provided, single submitter clinical testing
Invitae RCV000791367 SCV000553380 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-09-08 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the VHL mRNA at codon 161 (p.Arg161*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 53 amino acid residues of the VHL protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with von Hippel-Lindau (VHL) syndrome (PMID: 7987306, 12114495, 25867206, 15300849, 9829911, 9829912) and VHL-related disease (PMID: 19270817, 10567493), including as de novo in two affected individuals (PMID: 14722919, 24206762), and segregates with disease in several families (PMID: 9452032, 8956040, 21362373, 18446368, 24301059). This variant is also known as c.694C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 2217). This truncation deletes a significant portion of the VHL elongin binding domain (PMID: 14987375), which is required for protein stability and tumor suppressive activity (PMID: 10900011). Experimental studies have shown that missense substitutions in this domain (p.Arg161Gln, p.Cys162Trp, p.Arg167Gly, p.Arg167Trp, p.Arg167Gln) impair protein function in vitro (PMID: 25371412, 21715564, 17350623, 19602254, 15574766, 19030229, 19252526, 14973063), indicating that the amino acid residues deleted by this truncating variant are important for protein function. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000492225 SCV000580965 pathogenic Hereditary cancer-predisposing syndrome 2018-07-02 criteria provided, single submitter clinical testing The p.R161* pathogenic mutation (also known as c.481C>T) located in coding exon 3 of the VHL gene, results from a C to T substitution at nucleotide position 481. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation has been reported in several individuals with personal and family histories of Von Hippel-Lindau (VHL) syndrome <span style="background-color:initial">(Cho HJ et al. J Korean Med Sci. 2009 Feb;24:77-83; Siu WK et al. Chin. Med. J. 2011 Jan;124:237-41; Zbar B et al. Hum. Mutat. 1996;8:348-57; Papathomas TG et al. Mod. Pathol. 2015 Jun;28:807-21; Wong M et al. Chin J Cancer. 2016 Aug;35:79; Sriphrapradang C et al. Clin Med Insights Endocrinol Diabetes. 2017 Apr;10:1179551417705122). A 48 year old male with bilateral renal clear cell carcinoma and a clinical diagnosis of VHL was found to be a mosaic carrier of this pathogenic mutation (Coppin L et al. Eur. J. Hum. Genet<span style="background-color:initial">. 2014 Sept;22:1149-52). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000161091 SCV000884875 pathogenic not provided 2018-04-16 criteria provided, single submitter clinical testing The VHL c.481C>T; p.Arg161Ter variant (rs5030818), also known as c.694C>T for traditional nomenclature, is reported multiple times in the literature in association with von Hippel-Lindau disease (see Cybulski 2002, Glavac 1996, Nordstrom-O'Brien 2010, Stolle 1998, Zbar 1996). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 2217), and it is absent from the general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-medicated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Cybulski C et al. Germline mutations in the von Hippel-Lindau (VHL) gene in patients from Poland: disease presentation in patients with deletions of the entire VHL gene. J Med Genet. 2002 Jul;39(7):E38. Glavac D et al. Mutations in the VHL tumor suppressor gene and associated lesions in families with von Hippel-Lindau disease from central Europe. Hum Genet. 1996 Sep;98(3):271-80. Nordstrom-O'Brien M et al. Genetic analysis of von Hippel-Lindau disease. Hum Mutat. 2010 May;31(5):521-37. Stolle C et al. Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum Mutat. 1998;12(6):417-23. Zbar B et al. Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat. 1996;8(4):348-57.
University Health Network Clinical Genomics Labs,University Health Network RCV000002301 SCV001950138 pathogenic Von Hippel-Lindau syndrome 2018-05-04 criteria provided, single submitter clinical testing
OMIM RCV000002301 SCV000022459 pathogenic Von Hippel-Lindau syndrome 1995-12-01 no assertion criteria provided literature only
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000002301 SCV000060202 pathogenic Von Hippel-Lindau syndrome 2007-10-16 no assertion criteria provided clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000002301 SCV000264756 pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing
Database of Curated Mutations (DoCM) RCV000437445 SCV000505322 likely pathogenic Renal cell carcinoma, papillary, 1 2015-07-14 no assertion criteria provided literature only
Neuromuscular Department, Shariati Hospital, Tehran University of Medical Sciences RCV001280922 SCV001450647 pathogenic Familial infantile myasthenia 2017-12-27 no assertion criteria provided clinical testing

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