Submissions for variant NM_000551.3(VHL):c.341-3T>G (rs1131690965)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492211	SCV000580991	likely pathogenic	Hereditary cancer-predisposing syndrome	2016-05-04	criteria provided, single submitter	clinical testing	The c.341-3T>G intronic variant results from a T to G substitution 3 nucleotides upstream from coding exon 2 in the VHL gene. Another alteration located in the same region and expected to affect the same splice site,c.341-1G>A,has been identified in individuals with vonHippel-Lindau(VHL) and has been shown through functional studies to lead to a skipping ofexon2 (GomyI,Fam. Cancer2010Dec; 9(4):635-42).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 0.01% (greater than 12000alleles tested) in our clinical cohort. Based on nucleotide sequence alignment, this nucleotide position is well conserved in available vertebrate species. Using theBDGPandESEfindersplice site prediction tools,this alterationpredicts that this alteration will abolish the native splice acceptor site; however, directevidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia	RCV000767259	SCV000897808	uncertain significance	Von Hippel-Lindau syndrome	2018-08-01	criteria provided, single submitter	clinical testing