ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.408T>G (p.Phe136Leu) (rs878854125)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000231504 SCV000285496 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2020-08-15 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 136 of the VHL protein (p.Phe136Leu). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with VHL-related disease. ClinVar contains an entry for this variant (Variation ID: 238107). Experimental in-vitro studies have shown that this missense change results in impaired folding, stability and function of the VHL protein (PMID: 23840444). However, the clinical significance of this finding is unclear. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000563379 SCV000675807 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-25 criteria provided, single submitter clinical testing The p.F136L variant (also known as c.408T>G), located in coding exon 2 of the VHL gene, results from a T to G substitution at nucleotide position 408. The phenylalanine at codon 136 is replaced by leucine, an amino acid with highly similar properties. A functional study predicts that this variant is likely to cause misfolding of the pVHL protein (Shmueli MD et al. PLoS ONE, 2013 Jun;8:e66333). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV001562617 SCV001785410 uncertain significance not provided 2020-02-11 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with breast and/or ovarian cancer (Maxwell 2016); This variant is associated with the following publications: (PMID: 30194449, 23819521, 20052764, 28188106, 27153395, 15932632, 20151405, 23840444)

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