Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV002504206 | SCV002817171 | uncertain significance | Hypercholesterolemia, familial, 1 | 2022-08-29 | reviewed by expert panel | curation | The NM_000527.5(LDLR):c.770G>A (p.Arg257Gln) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and BP4 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 - PopMax MAF = 0.00004395 (0.004395%) in European non-Finnish exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. BP4 - REVEL = 0.279, it is below 0.50, splicing evaluation required. Functional data on splicing not available. A) not on limits B) does not create GT C) there are no GT nearby variant is predicted to not alter splicing, so BP4 is met. |
Color Diagnostics, |
RCV001190237 | SCV001357684 | uncertain significance | Familial hypercholesterolemia | 2023-04-27 | criteria provided, single submitter | clinical testing | This missense variant (also known as p.Arg236Gln in the mature protein) replaces arginine with glutamine at codon 257 of the LDLR 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 been reported in individuals affected with familial hypercholesterolemia (PMID: 34407635). This variant has been identified in 5/251480 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. |
Fulgent Genetics, |
RCV002504206 | SCV002815242 | uncertain significance | Hypercholesterolemia, familial, 1 | 2021-11-24 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV003478725 | SCV004219998 | uncertain significance | not provided | 2023-08-04 | criteria provided, single submitter | clinical testing | In the published literature, this variant has been reported in familial hypercholesterolemia (PMID: 34407635 (2021)). The frequency of this variant in the general population, 0.000044 (5/113758 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. |
All of Us Research Program, |
RCV002504206 | SCV004820212 | uncertain significance | Hypercholesterolemia, familial, 1 | 2023-10-02 | criteria provided, single submitter | clinical testing | This missense variant (also known as p.Arg236Gln in the mature protein) replaces arginine with glutamine at codon 257 of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 5/251480 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. |