ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000558602 SCV000626889 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-01-08 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 several individuals affected with Von Hippel-Lindau syndrome (PMID: 10567493, 7728151, 17024664, 8956040). 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>C) giving rise to the same protein effect observed here (p.Trp88Arg) has been reported in individuals affected with Von Hippel-Lindau syndrome (PMID: 12624160, 17688370, Invitae). 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.
Integrated Genetics/Laboratory Corporation of America RCV000587190 SCV000697493 pathogenic Von Hippel-Lindau syndrome 2016-02-03 criteria provided, single submitter clinical testing Variant summary: This c.262T>A variant affects a conserved nucleotide, resulting in amino acid change from Trp to Arg in beta domain of VHL protein. 5/5 in-silico tools predict this variant to be damaging. This variant was not found in approximately 102226 control chromosomes including the large and broad populations from ExAC. This variant has been reported in at least ten independent VHL patients, two of whom carried the variant as somatic occurrence. In a family, the variant was found in two affected members, suggesting a possible cosegregation of the variant with disease (Glasker_2001). Another nucleotide change leading to the same amino acid change c.262T>C is a pathogenic variant, a strong evidence that this nucleotide change 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. Taken together, this variant has been classified as a Pathogenic.
PreventionGenetics,PreventionGenetics RCV000679026 SCV000805333 pathogenic not provided 2014-04-16 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000587190 SCV000897793 pathogenic Von Hippel-Lindau syndrome 2018-08-01 criteria provided, single submitter clinical testing

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