Submissions for variant NM_000551.4(VHL):c.340+1G>A

dbSNP: rs730882032

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001044454	SCV001208252	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-07-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. RNA analysis provides insufficient evidence to determine the effect of this variant on VHL splicing (Invitae). ClinVar contains an entry for this variant (Variation ID: 223190). This variant is also known as IVS1+1G>A. Disruption of this splice site has been observed in individuals with clinical features of von Hippel-Lindau syndrome (PMID: 9829912, 20518900, 20850701, 27527340, 30900640; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor 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).
Ambry Genetics	RCV004020566	SCV003625919	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-03	criteria provided, single submitter	clinical testing	The c.340+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 1 of the VHL gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration (also known as c.553+1G>A and IVS+1G>A) was reported in multiple individuals meeting clinical criteria for Von Hippel-Lindau syndrome (VHLS) (Dollfus, 2002; Palui, 2019; Ambry internal data) and multiple additional individuals with primary features of VHLS (Olschwang, 1998; Cybulski, 2004; Rao, 2010; Zhou, 2010). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. Based on the available evidence, this alteration is classified as pathogenic.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000208808	SCV000264713	pathogenic	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001701877	SCV001931297	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001701877	SCV001957124	pathogenic	not provided		no assertion criteria provided	clinical testing