ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.634G>T (p.Gly212Ter) (rs1553620389)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000508553 SCV000605564 uncertain significance not specified 2017-03-14 criteria provided, single submitter clinical testing
Invitae RCV000556062 SCV000626915 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2017-06-17 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the VHL gene (p.Gly212*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 2 amino acids of the VHL protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a VHL-related disease. 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, this variant has uncertain impact on VHL function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000575054 SCV000675815 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-18 criteria provided, single submitter clinical testing The p.G212* variant (also known as c.634G>T), located in coding exon 3 of the VHL gene, results from a G to T substitution at nucleotide position 634. This changes the amino acid from a glycine to a stop codon within coding exon 3.This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position.Premature stopcodonsare typically deleterious in nature, however,<span style="font-family:arial,sans-serif; font-size:10pt"><span style="font-family:arial,sans-serif; font-size:10pt">this stopcodonoccurs at the 3' terminus of<span style="font-family:arial,sans-serif; font-size:10pt">VHL<span style="font-family:arial,sans-serif; font-size:10pt">, is not expected to trigger nonsense mediated decay (NMD), and impacts only the last twoamino acids of the protein(MaquatLE et al.Nat. Rev. Mol. Cell<span style="font-family:arial,sans-serif; font-size:10pt">Biol<span style="font-family:arial,sans-serif; font-size:10pt">.<span style="font-family:arial,sans-serif; font-size:10pt">2004 Feb; 5(2):89-99).Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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