Submissions for variant NM_000551.4(VHL):c.341-2A>G

dbSNP: rs869025637

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen VHL Variant Curation Expert Panel, ClinGen	RCV000208784	SCV005187315	pathogenic	Von Hippel-Lindau syndrome	2024-06-25	reviewed by expert panel	curation	The variant NM_000551.3(VHL):c.341-2A>G is a canonical splice site within the 1st intron of the VHL gene, and is predicted to undergo nonsense mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 3 studies, in cases or families with VHL syndrome or VHL-related cancers. PMIDs: 17661816, 17024664, 27539324, CIViC EIDs (https://civicdb.org): 5748, 5730. Two commercial laboratories report 1 case each, both with a history of VHL-related cancers. One had an additional clinical diagnosis of VHL and a first degree relative with multiple VHL-related cancers in age 30-40yrs who was also VHL positive (PS4_Moderate). Although PP3 was not applied due to use of PVS1, we include the note that multiple splice predictors were used to evaluate the splice site. VarSeak supports the impact of disrupting this canonical splice site (Class 5) and the Splice AI score is 0.93, indicating impact on splicing. In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001034627	SCV000626872	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2022-03-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.341-2A nucleotide in the VHL gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 17024664). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 223194). Disruption of this splice site has been observed in individuals with unilateral pheochromocytoma (PMID: 27539324). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 1 of the VHL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in VHL are known to be pathogenic (PMID: 8956040, 12202531, 29891534, 31350093).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000208784	SCV000918339	pathogenic	Von Hippel-Lindau syndrome	2022-03-28	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 251496 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 (e.g. 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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000208784	SCV000264718	pathogenic	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing