Submissions for variant NM_000551.4(VHL):c.194C>A (p.Ser65Ter)

dbSNP: rs5030826

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001213116	SCV001384733	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2019-09-23	criteria provided, single submitter	clinical testing	This variant has been observed in families affected with von Hippel-Lindau disease (PMID: 7977367). This variant is also known as 407T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 223161). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser65*) in the VHL gene. It is expected to result in an absent or disrupted protein product. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in VHL are known to be pathogenic (PMID: 8956040, 12202531).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509303	SCV002819570	pathogenic	Chuvash polycythemia	2022-12-15	criteria provided, single submitter	clinical testing	Variant summary: VHL c.194C>A (p.Ser65X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 221788 control chromosomes (gnomAD). c.194C>A (also known as c.407C>A) has been reported in the literature in individuals affected with Von Hippel-Lindau Syndrome (e.g. Whaley_1994, Zbar_1996, Stolle_1998, Glasker_1999, Klein_2001). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)	RCV000208831	SCV003930410	pathogenic	Von Hippel-Lindau syndrome	2023-05-21	criteria provided, single submitter	clinical testing
GeneDx	RCV003233497	SCV003930932	pathogenic	not provided	2022-12-05	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.407C>A, p.(S136*) and p.(S106*); This variant is associated with the following publications: (PMID: 10408776, 7977367, 35205407, 28379443, 9829911)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000208831	SCV000264668	pathogenic	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing