Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000508796 | SCV004022385 | uncertain significance | Hypercholesterolemia, familial, 1 | 2023-03-20 | reviewed by expert panel | curation | The NM_000527.5 (LDLR):c.2530G>A (p.Gly844Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD 2.1.1). PP3: REVEL = 0.875. PM5 not met: One other variant in the same codon: -NM_000527.5:c.2531G>A (Gly844Asp) is classified as Likely Pathogenic by these guidelines, therefore PM5 is not met. |
| Labcorp Genetics |
RCV002527377 | SCV003454975 | uncertain significance | Familial hypercholesterolemia | 2022-07-17 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 844 of the LDLR protein (p.Gly844Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LDLR-related conditions. ClinVar contains an entry for this variant (Variation ID: 440701). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Gly844 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7573037). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |
| All of Us Research Program, |
RCV000508796 | SCV004820692 | uncertain significance | Hypercholesterolemia, familial, 1 | 2023-10-30 | criteria provided, single submitter | clinical testing | This missense variant (also known as p.Gly823Ser in the mature protein) replaces glycine with serine at codon 844 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with familial hypercholesterolemia (PMID: 36499307). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Gly844Asp, is known to be disease-causing (ClinVar variation ID: 3734), indicating that glycine at this position is important for LDLR protein function. 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. |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000508796 | SCV000606665 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |