ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.262T>C (p.Trp88Arg) (rs1553619431)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000589476 SCV000697494 pathogenic Von Hippel-Lindau syndrome 2016-02-03 criteria provided, single submitter clinical testing Variant summary: This c.262T>C variant affects a conserved nucleotide, resulting in amino acid change from Trp to Arg. 5/5 in-silico tools predict this variant to be damaging. This variant was not found in approximately 102034 control chromosomes, including the large and broad populations from ExAC. This variant has been reported in at least seven unrelated VHL patients and VHL-related tumors. c.262T>A, another variant leading to the same amino acid change, is a pathogenic variant. This evidence strongly supports that variant of interest is also pathogenic. In addition, codon 88 is a mutational hot spot in which other potentially pathogenic variants such as .W88C, p.W88S, p.W88* (c.263G>A) and p.W88* (c.264G>A) have been reported in VHL disease or its related cancers. In a tumor cell containing this variant, vascular endothelial growth factor (VEGF) expression was significantly increased which suggests that this variant leads to functional impairment (although it is uncertain whether observed effect was solely due to this variant as they assay was from patient cells) (Na_2003). Taken together, this variant has been classified as a Pathogenic.
Invitae RCV000631292 SCV000752320 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-05-24 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 88 of the VHL protein (p.Trp88Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with Von Hippel-Lindau syndrome (PMID: 12624160, 17688370). This variant is also known in the literature as c.475T>C. 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different variant (c.262T>A) giving rise to the same protein effect observed here (p.Trp88Arg) has been reported in individuals affected with Von Hippel-Lindau syndrome (PMID: 17024664, 11309459, 7728151, 19996202, 10567493, 27530247). In addition, a different missense substitution at this codon (p.Trp88Cys) has been determined to be likely pathogenic (PMID: 10567493, 21715564). This suggests that the tryptophan residue is critical for VHL protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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