Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000780788 | SCV000918342 | pathogenic | Von Hippel-Lindau syndrome | 2018-10-19 | criteria provided, single submitter | clinical testing | Variant summary: VHL c.331A>G (p.Ser111Gly) results in a non-conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, beta domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 217656 control chromosomes (gnomAD and publication). c.331A>G has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome (Whaley_1994, Bradley_2009, Young_2009). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal activity (Domene_2012, Perier_2011). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Although, additional variants affecting the same codon, p.S111R, p.S111C, S111N, and S111I, have been reported in HGMD and ClinVar as pathogenic, therefore, suggesting a mutational hot spot. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Invitae | RCV001039507 | SCV001203039 | pathogenic | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2020-11-23 | criteria provided, single submitter | clinical testing | 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: 12202531, 12807974, 22071692). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect VHL protein function (PMID: 21258414). This variant has been observed in individual(s) with clinical features of von Hippel Lindau syndrome (PMID: 19293973, 9209471, Invitae). In at least one individual the variant was observed to be de novo. The variant is also known as 554A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 633016). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with glycine at codon 111 of the VHL protein (p.Ser111Gly). The serine residue is moderately conserved and there is a small physicochemical difference between serine and glycine. |