ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.497T>C (p.Val166Ala) (rs397516445)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036549 SCV000060204 pathogenic Von Hippel-Lindau syndrome 2012-09-11 criteria provided, single submitter clinical testing The Val166Ala variant has previously been reported to have occurred de novo in a n individual with clinical features of Von Hippel-Lindau syndrome and has been i dentified in one affected individual previously tested by our laboratory (Hes 20 07, LMM unpublished data). Valine (Val) at position 166 is not evolutionarily co nserved in mammals (rabbit and pika have an isoleucine at this position), howeve r, a different amino acid change at this location (Val166Phe) has also been asso ciated with the clinical features of Von Hippel-Lindau syndrome (Maher 1996). Co mputational analyses (biochemical amino acid properties, conservation, AlignGVGD , PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein, but structural evidence suggests this amino acid plays an importan t role in VHL function (Stebbins 1999). In summary, this variant is highly likel y to be pathogenic based on its de novo occurrence in a patient with sporadic di sease.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000036549 SCV000897837 pathogenic Von Hippel-Lindau syndrome 2018-08-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV001023359 SCV001185223 likely pathogenic Hereditary cancer-predisposing syndrome 2018-03-07 criteria provided, single submitter clinical testing The p.V166A variant (also known as c.497T>C), located in coding exon 3 of the VHL gene, results from a T to C substitution at nucleotide position 497. The valine at codon 166 is replaced by alanine, an amino acid with similar properties. This alteration was detected in an individual diagnosed with bilateral pheochromocytomas at age 11 (Hes FJ et al. Clin. Genet., 2007 Aug;72:122-9). Another mutation at the same position, p.V166F, has been described in multiple individuals with a clinical diagnosis of Von Hippel-Lindau syndrome (Cruz JB et al, Arq Bras Endocrinol Metabol 2007 Dec; 51(9):1463-7; Gross DJ et al. J. Clin. Endocrinol. Metab. 1996 Jan; 81(1):147-9; Nordstrom-O'Brien M et al. Hum. Mutat. 2010 May;31(5):521-37; Maher ER et al. J. Med. Genet. 1996 Apr; 33(4):328-32). The p.V166A alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. In addition, this alteration is predicted to disrupt enlogin C interaction of pVHL (Forman JR et al. Proteins, 2009 Oct;77:84-96). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV001701727 SCV001932465 pathogenic not provided no assertion criteria provided clinical testing

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