Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000804483 | SCV000944394 | pathogenic | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2018-10-01 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Experimental studies have shown that this missense change affects HIF1 alpha degradation due to a reduced interaction with TBP1 and the proteasome (PMID: 14556007). This variant has been observed in several individuals and families affected with von Hippel-Lindau syndrome (PMID: 20660572, 23143947, 7987306, 25867206, 17024664, 8956040). This variant is also known as c.674C>T (p.Pro225Leu) in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 154 of the VHL protein (p.Pro154Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. |
| Ambry Genetics | RCV002336632 | SCV002635513 | pathogenic | Hereditary cancer-predisposing syndrome | 2014-10-15 | criteria provided, single submitter | clinical testing | The p.P154L pathogenic mutation (also known as c.461C>T), located in coding exon 2 of the VHL gene, results from a C to T substitution at nucleotide position 461. The proline at codon 154 is replaced by leucine, an amino acid with very few similar properties. This alteration has been reported in several affected individuals/families (Crossey PA et al. Hum Mol Genet. 1994 Aug;3(8):1303-8; Whaley JM et al. Am J Hum Genet. 1994 Dec;55(6):1092-102; Banks RE et al. Cancer Res. 2006 Feb 15;66(4):2000-11; Ong KR et al. Hum Mutat. 2007 Feb;28(2):143-9). This alteration was also reported in two family members diagnosed with renal cell carcinoma, and both tumors exhibited loss of heterozygocity for this allele (Prowse AH et al. Am J Hum Genet. 1997 Apr;60(4):765-71). Truncation experiments suggest that this region is critical for p53 binding (Roe JS et al. Mol Cell. 2006 May 5;22(3):395-405). Functional analysis of this variant showed restored FGFR1 internalization and Elongin C binding similar to the wild type allele, however HIF degradation/ubiquitination was similar to that of the null mutant (Hsu T et al. J Biol Chem. 2006 Apr 28;281(17):12069-80). Structural bioinformatics mutation analysis predicts that this variant will leave an unsatisfied hydrogen bonding partner in the main chain of pVHL and that this will significantly change the protein folding altering or preventing required protein interactions (Forman JR et al. Proteins. 2009 Oct;77(1):84-96). This variant is also referred to as p.P225L (c.674C>T) in older literature. Based on the available evidence, p.P154L is classified as a pathogenic mutation. |