Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000780787 | SCV000918340 | likely pathogenic | Von Hippel-Lindau syndrome | 2017-09-01 | criteria provided, single submitter | clinical testing | Variant summary: The VHL c.336C>G (p.Tyr112X) variant results in a premature termination codon, predicted to cause a truncated or absent VHL 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 (e.g. c.337C>T (p.Arg113X), c.384delT (p.Leu129fsX30), and c.394C>T (p.Gln132X)). A publication, Chen_1996 cites the variant c.336C>A, which causes the same nonsense mutation in two patients diagnosed with VHL. This variant is absent in 91896 control chromosomes from ExAC. This nucleotide change has not, to our knowledge, been reported in reputable databases and/or clinical diagnostic laboratories. Taken together, this variant is classified as likely pathogenic. |
| Invitae | RCV001068352 | SCV001233459 | pathogenic | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2019-03-04 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in VHL are known to be pathogenic (PMID: 8956040, 12202531). This variant has not been reported in the literature in individuals with VHL-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr112*) in the VHL gene. It is expected to result in an absent or disrupted protein product. |
| Ambry Genetics | RCV003307415 | SCV004006354 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-05-04 | criteria provided, single submitter | clinical testing | The p.Y112* pathogenic mutation (also known as c.336C>G), located in coding exon 1 of the VHL gene, results from a C to G substitution at nucleotide position 336. This changes the amino acid from a tyrosine to a stop codon within coding exon 1. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with VHL-related disease (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. |