Submissions for variant NM_000551.3(VHL):c.497T>C (p.Val166Ala) (rs397516445)

Total submissions: 2

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syndrome and has been i dentified in one affected individual previously tested by our laboratory (Hes 20 07, LMM unpublished data).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.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia	RCV000036549	SCV000897837	pathogenic	Von Hippel-Lindau syndrome	2018-08-01	criteria provided, single submitter	clinical testing