ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.224T>G (p.Ile75Ser) (rs1064794271)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479941 SCV000568590 uncertain significance not provided 2016-08-03 criteria provided, single submitter clinical testing This variant is denoted VHL c.224T>G at the cDNA level, p.Ile75Ser (I75S) at the protein level, and results in the change of an Isoleucine to a Serine (ATC>AGC). This variant was observed in at least one individual suspected of having von Hippel-Lindau (VHL) with no additional clinical information provided (Ong 2007). VHL Ile75Ser 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 Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. VHL Ile75Ser occurs at a position that is conserved in mammals and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Splicing models suggest that a cryptic splice donor site is created upstream of the natural splice donor site; however the natural splice donor site is not predicted to be changed. In the absence of RNA or functional studies, the actual effect of this variant on splicing is unknown. Based on currently available evidence, it is unclear whether VHL Ile75Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000767237 SCV000897780 uncertain significance Von Hippel-Lindau syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV001201718 SCV001372804 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-09-24 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with serine at codon 75 of the VHL protein (p.Ile75Ser). The isoleucine residue is moderately conserved and there is a large physicochemical difference between isoleucine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals suspected with von Hippel-Lindau disease (PMID: 17024664, Invitae). ClinVar contains an entry for this variant (Variation ID: 420073). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional 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.

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