Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000492721 | SCV000580976 | pathogenic | Hereditary cancer-predisposing syndrome | 2013-06-07 | criteria provided, single submitter | clinical testing | The p.S111N mutation (also known as c.332G>A) is located in exon 1 of the VHL gene. This alteration results from a G to A substitution at nucleotide position 332. The serine at codon 111 is replaced by asparagine, an amino acid with similar properties. This mutation has been reported in many VHL families affected with retinal angiomas, CNS hemangioblastomas, and renal cell carcinoma. None of the families in the literature had a history of pheochromocytomas which would fit the clinical description of VHL Type 1 (Chen et al. Human Mutation. 1995. 5:66-75; Maher et al. J Med Genet. 1996: 33328-332; Zbar et al. Human Mutation. 1996. 8:348-357; Ong et al. Human Mutation. 2007. 28(2):143-149; Zhang et al. J Cancer Res Clin Oncol. 2008. 134:1211-1218). Based on the available evidence, p.S111N is classified as a pathogenic mutation. This mutation has been referred to as p.S182N (c.545G>A) in older literature. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000208834 | SCV000697498 | pathogenic | Von Hippel-Lindau syndrome | 2016-02-05 | criteria provided, single submitter | clinical testing | Variant summary: This c.332G>A variant affects a conserved nucleotide, resulting in amino acid change from Ser to Asn. Although 4/4 in-silico tools predict this variant to be benign, no functional studies have been performed to confirm these predictions. This variant was not found in approximately 92088 control chromosomes including the broad and large populations from ExAC. In literature, the variant has been widely reported as a pathogenic variant found in several patients/families with VHL disease, including somatic occurrences. This p.Ser111 is likely to be a mutational hot-spot where other likely pathogenic variant [such as p.S111R (c.331A>C and c.333C>G), p.S111C, p.S111I, etc.] have also been reported. At least one reputable database classifies the variant as pathogenic. Taken together, this variant has been classified as a Pathogenic. |
| Invitae | RCV002517414 | SCV003525038 | pathogenic | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2022-04-02 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 111 of the VHL protein (p.Ser111Asn). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser111 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7728151, 12114495, 16868829, 22071692, 25562111; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function. ClinVar contains an entry for this variant (Variation ID: 223186). This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 7728151, 27527340, 28849724). This variant is not present in population databases (gnomAD no frequency). |
| Genomic Diagnostic Laboratory, |
RCV000208834 | SCV000264708 | pathogenic | Von Hippel-Lindau syndrome | 2016-02-26 | no assertion criteria provided | clinical testing |