Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000822511 | SCV000963318 | pathogenic | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2023-08-04 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 115 of the VHL protein (p.His115Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 8707293, 22357542). This variant is also known as 557A>G. ClinVar contains an entry for this variant (Variation ID: 664415). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on VHL function (PMID: 14556007). This variant disrupts the p.His115 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 7728151, 9829912, 12202531, 17024664, 29749453), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV003169035 | SCV003888322 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-11-16 | criteria provided, single submitter | clinical testing | The p.H115R pathogenic mutation (also known as c.344A>G), located in coding exon 2 of the VHL gene, results from an A to G substitution at nucleotide position 344. The histidine at codon 115 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with a clinical diagnosis of von Hippel-Lindau disease (VHL) (Glavac D et al. Hum Genet, 1996 Sep;98:271-80; Wu P et al. J Hum Genet, 2012 Apr;57:238-43). This variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with VHL (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |