ClinVar Genomic variation as it relates to human health

ClinVar contains an entry for this variant (Variation ID: 428795). This variant is also known as 746T>C (p.L249P). This missense change has been observed in individuals with von Hippel-Lindau disease (PMID: 17024664, 19464396, 19763184, 27527340). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 178 of the VHL protein (p.Leu178Pro). 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. For these reasons, this variant has been classified as Pathogenic.

The p.L178P pathogenic mutation (also known as c.533T>C), located in coding exon 3 of the VHL gene, results from a T to C substitution at nucleotide position 533. The leucine at codon 178 is replaced by proline, an amino acid with some similar properties. This alteration has been reported in multiple individuals with personal and/or family history consistent with Von Hippel-Lindau syndrome (VHL) both with and without pheochromocytoma (Crossey PA et al. Hum. Mol. Genet. 1994 Aug3(8):1303-8; Erlic et al. Endocrine-Related Cancer. 2010. 17;875-883; Gläsker S et al. J. Neurol. Neurosurg. Psychiatr. 1999 Dec;67(6):758-62; Ong KR et al. Hum. Mutat. 2007 Feb;28(2):143-9; Zbar B et al. Hum. Mutat. 1996;8(4):348-57; Krauss T et al. Endocr Relat Cancer, 2018 09;25:783-793; Bausch B et al. Head Neck, 2016 04;38 Suppl 1:E673-9; Ciotti P et al. Eur J Med Genet May;52:311-4; Ambry internal data). This alteration has also been reported in individuals with personal history of pheochromocytoma or functional paraganglioma but without a formal diagnosis of VHL syndrome (Amar L et al. J. Clin. Oncol. 2005 Dec;23(34):8812-8). In the literature, this alteration has also been referred to as a common VHL germline mutation (Cybulski C et al. J. Med. Genet. 2002 Jul;39(7):E38; López-Guerrero JA et al. Adv Urol 2008:720840). Of note, this alteration is also designated as 746T>C in some published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

The c.533T>C (p.Leu178Pro) variant in the VHL gene is located on the exon 3 and is predicted to replace leucine with proline at codon 178 (p.Leu178Pro). The variant has been reported in multiple unrelated individuals with von Hippel–Lindau disease and/or pheochromocytoma and segregate with disease (PMID: 31383958, 25867206, 19464396, 8956040, 9452106). An alternative variant disrupting the same amino acid (p.Leu178Arg) has been reported in individuals with Von Hippel-Lindau disease and interpreted as pathogenic (ClinVar ID: 625261). The variant is reported in ClinVar (ID: 428795). The variant is absent in the general population database (gnomAD). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.951). Therefore, the c.533T>C (p.Leu178Pro) variant of VHL has been classified as pathogenic.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8634692, 12114495, 7987306, 33415482, 25563310, 18836774, 11058902, 19009041, 19763184, 29748190, 36316043, 35466127, 27527340, 16314641, 14722919, 8956040, 7728151, 10567493, 8707293, 17024664, 7553625, 10408776, 25867206, 19464396, 10761708, 21972040)