Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV001294070 | SCV005187293 | likely benign | Von Hippel-Lindau syndrome | 2024-06-25 | reviewed by expert panel | curation | The variant NM_000551.4(VHL):c.89G>A (p.Gly30Glu) is a missense variant predicted to cause substitution of Glycine by Glutamic Acid at position 30. This is prior to the second start site at codon 54. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.0001073 (10/50204 from Admixed American Population). This is higher than the ClinGen VHL VCEP threshold of >=0.0000156 (0.00156%) threshold expected for VHL disease (BS1). In addition, one commercial laboratory reports at least 3 cases over 60+ with no VHL spectrum tumors, and another commercial laboratory reports too many cases over 65+ without VHL spectrum tumors to review (of 35 cases with no VHL spectrum tumors). The VHL VCEP has determined this meets (BS2_Supporting) due to the number of cases, ages and lack of information on full VHL screening/phenotyping. In summary, this variant meets the criteria to be classified as Likely Benign for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). |
Gene |
RCV001712442 | SCV000565654 | likely benign | not provided | 2021-01-10 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000696976 | SCV000825562 | uncertain significance | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2023-12-27 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 30 of the VHL protein (p.Gly30Glu). This variant is present in population databases (no rsID available, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with VHL-related conditions. ClinVar contains an entry for this variant (Variation ID: 418538). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on VHL protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
Ambry Genetics | RCV001018619 | SCV001179876 | likely benign | Hereditary cancer-predisposing syndrome | 2021-08-13 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
Baylor Genetics | RCV001294070 | SCV001482870 | uncertain significance | Von Hippel-Lindau syndrome | 2019-02-21 | criteria provided, single submitter | clinical testing | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV001712442 | SCV002774877 | uncertain significance | not provided | 2021-07-20 | criteria provided, single submitter | clinical testing | |
Ce |
RCV001712442 | SCV004146914 | uncertain significance | not provided | 2022-08-01 | criteria provided, single submitter | clinical testing | VHL: PM2:Supporting, BP4 |
Prevention |
RCV003900013 | SCV004717003 | uncertain significance | VHL-related disorder | 2024-01-16 | criteria provided, single submitter | clinical testing | The VHL c.89G>A variant is predicted to result in the amino acid substitution p.Gly30Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |
All of Us Research Program, |
RCV001294070 | SCV004827698 | uncertain significance | Von Hippel-Lindau syndrome | 2024-01-11 | criteria provided, single submitter | clinical testing | This missense variant replaces glycine with glutamic acid at codon 30 of the VHL protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with VHL-related disorders in the literature. This variant has been identified in 7/176170 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |