ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.414A>G (p.Pro138=) (rs869025648)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216698 SCV000276962 pathogenic Hereditary cancer-predisposing syndrome 2018-12-20 criteria provided, single submitter clinical testing The c.414A>G pathogenic mutation (also known as p.P138P), located in coding exon 2, results from an A to G substitution at nucleotide position 414 of the VHL gene. This nucleotide substitution does not change the amino acid at codon 138. This alteration was identified in multiple individuals affected with pheochromocytomas or von Hippel-Lindau syndrome from two unrelated three-generation families and showed segregation with disease and loss of heterozygosity in one tumor sample (Lenglet M et al. Blood. 2018 Aug;132:469-483). RT-PCR analysis of patient samples and minigene assays show this alteration leads to skipping of exon 2. This alteration has been identified in numerous patients with pheochromocytomas, or a clinical diagnosis of von Hippel-Lindau syndrome (Ambry internal data, Ambry personal communication). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000469600 SCV000553422 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-11-06 criteria provided, single submitter clinical testing This sequence change affects codon 138 of the VHL mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the VHL protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with von Hippel-Lindau (VHL) syndrome-associated tumors in several families (PMID: 29891534). This variant has also been observed in individuals with a personal and/or family history of VHL syndrome-associated tumors (Invitae). This variant is also known as P138P in the literature. ClinVar contains an entry for this variant (Variation ID: 223206). Experimental studies have shown that this silent change causes an increase of the alternative VHL transcript with skipping of exon 2 in both patient-derived cells and minigene assays (PMID: 29891534). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001636725 SCV001851420 pathogenic not provided 2021-05-28 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: skipping of exon 2 resulting in increased expression of the isoform lacking exon 2 and an increased expression of target genes (Lenglet 2018, Flores 2019, Liu 2020); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29891534, 30946460, 32106822, 33362715, 25825477, 33151962)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000208865 SCV000264732 likely pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing
OMIM RCV000208865 SCV001167313 pathogenic Von Hippel-Lindau syndrome 2020-03-05 no assertion criteria provided literature only

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