ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.341-2A>G (rs869025637)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000208784 SCV000264718 pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000208784 SCV000918339 pathogenic Von Hippel-Lindau syndrome 2018-05-08 criteria provided, single submitter clinical testing Variant summary: VHL c.341-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 3' canonical acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 246270 control chromosomes (gnomAD). The variant, c.341-2A>G, has been reported in the literature in multiple individuals affected with pheochromocytoma and renal cell carcinoma (Dalgliesh_2010, Garcias-Donas_2013, Pandit_2016, Razafinjatovo_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000208784 SCV000626872 pathogenic Von Hippel-Lindau syndrome 2017-03-08 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 1 of the VHL gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Loss-of-function variants in VHL are known to be pathogenic. This particular variant has been reported in the literature in an individual affected with unilateral pheochromocytoma (PMID: 27539324). A different variant affecting this nucleotide (c.341-2A>C) has been determined to be pathogenic (PMID: 17024664). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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