ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.487C>T (p.Leu163Phe) (rs1553620318)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000561095 SCV000664462 likely pathogenic Hereditary cancer-predisposing syndrome 2018-05-02 criteria provided, single submitter clinical testing The p.L163F variant (also known as c.487C>T), located in coding exon 3 of the VHL gene, results from a C to T substitution at nucleotide position 487. The leucine at codon 163 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration was reported in the literature in two unrelated individuals with pheochromocytomas (Tong AL et al, Ann. N. Y. Acad. Sci. 2006 Aug; 1073():203-7; Pandit R et al. Eur. J. Endocrinol., 2016 12;175:X3). Further, alterations at the same location, p.L163P and p.L163R, have been reported in individuals with presumed sporadic Von Hippel-Lindau (VHL), as well as isolated pheochromocytoma (Cho HJ et al, J. Korean Med. Sci. 2009 Feb; 24(1):77-83; Sans&oacute; G et al, Am. J. Hypertens. 2004 Dec; 17(12 Pt 1):1107-11). Based on internal structural assessment, this alteration destabilizes the VHL elongin binding domain (Van Molle I et al. Chem. Biol., 2012 Oct;19:1300-12). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. <br />
Invitae RCV001224534 SCV001396738 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-06-09 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 163 of the VHL protein (p.Leu163Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with clinical features of Von Hippel-Lindau syndrome (PMID: 29124493, 17102088, 25563310). This variant is also known as c.700C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 480772). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Leu163 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 15607616), which suggests that this may be a clinically significant amino acid residue. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001553667 SCV001774604 uncertain significance not specified 2021-07-12 criteria provided, single submitter clinical testing Variant summary: VHL c.487C>T (p.Leu163Phe) results in a non-conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, beta/alpha domain (IPR022772) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251440 control chromosomes (gnomAD). c.487C>T has been reported in the literature in individuals affected with pheochromocytoma or paraganglioma (e.g. Tong_2006, Pandit_2016, Goldstein_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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