Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000165774 | SCV000216519 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-03-25 | criteria provided, single submitter | clinical testing | The p.S80G variant (also known as c.238A>G), located in coding exon 1 of the VHL gene, results from an A to G substitution at nucleotide position 238. The serine at codon 80 is replaced by glycine, an amino acid with similar properties. This mutation was detected in a polish individual with bilateral pheochromocytoma (PCC) and absence of any other VHL clinical features. The patient's mother was also reported to have bilateral PCC (Woodward ER et al. Hum Mol Genet. 1997 Jul;6(7):1051-6). This alteration was also detected as a de novo mutation in a 12 year old male diagnosed with bilateral PCC and multiple congenital anomalies including microcephaly, severe hearing loss, and cryptorchidism, and developmental delay (Assadi F & Brackbill EL. Am J Kidney Dis. 2003 Jan;41(1):E3). This alteration was also observed as a somatic mutation in a PCC diagnosed in a 25 year old female (Crona J et al. PLoS One. 2014 Jan 22;9(1):e86756). Multiple other mutations at the same codon have been observed in individuals with Type 2 VHL (Ding X et al. J Neurosurg. 2014 Aug;121(2):384-6; Zhang J et al. J Cancer Res Clin Oncol. 2008 Nov;134(11):1211-8). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV001388793 | SCV001589931 | pathogenic | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2022-04-08 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser80 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 8707293, 27527340), which suggests that this may be a clinically significant amino acid residue. 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: 186220). This missense change has been observed in individual(s) with pheochromocytomas (PMID: 9215674, 12500216; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 80 of the VHL protein (p.Ser80Gly). |
| Clinical Genomics Labs, |
RCV002307423 | SCV002601726 | likely pathogenic | Von Hippel-Lindau syndrome | 2021-08-04 | no assertion criteria provided | clinical testing |