ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.440T>C (p.Ile147Thr) (rs1060503555)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000474921 SCV000553387 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2020-05-12 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 147 of the VHL protein (p.Ile147Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individuasl with sporadic pheochromocytoma (PMID: 9663592, 17102080). ClinVar contains an entry for this variant (Variation ID: 411964). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. 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.
GeneDx RCV000479163 SCV000568593 uncertain significance not provided 2016-05-06 criteria provided, single submitter clinical testing This variant is denoted VHL c.440T>C at the cDNA level, p.Ile147Thr (I147T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). This variant was observed in an individual with a unilateral pheochromocytoma (van der Harst 1998). VHL Ile147Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. VHL Ile147Thr occurs at a position that is not conserved and is located in the nuclear export/beta-domain as well as a region involved in binding to the CCT complex (Yuen 2009, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether VHL Ile147Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.

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