ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.397A>C (p.Thr133Pro) (rs1131690961)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492347 SCV000580986 likely pathogenic Hereditary cancer-predisposing syndrome 2015-03-06 criteria provided, single submitter clinical testing The p.T133P variant (also known as c.397A>C), located in coding exon 2 of the VHL gene, results from an A to C substitution at nucleotide position 397. The threonine at codon 133 is replaced by proline, an amino acid with highly similar properties. This variant has been described in two individuals with VHL (http://www.freidok.uni-freiburg.de/volltexte/3040/pdf/Dissertation_Hader_Claudia.pdf).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. To date, this alteration has been detected with an allele frequency of approximately 0.02% (greater than 4300 alleles tested) in our clinical cohort.This amino acid position is highly conserved in available vertebrate species. Structural analysis indicates proline introduces local strain andis destabilizing to the VHL fold (Nguyen HC et alStructure2015Mar;23(3):441-449)(Internal Ambry Data).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.

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