Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000237649 | SCV002817177 | uncertain significance | Hypercholesterolemia, familial, 1 | 2022-12-23 | reviewed by expert panel | curation | The NM_000527.5(LDLR):c.1954A>G (p.Met652Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and BS3_Supporting 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 follow: PM2_Met : Allele frequency is 0.00002 in European (Non-Finnish) subpopulation (>129178 alleles tested) in GnomAD (gnomAD v2.1.1). |
| Labcorp Genetics |
RCV006461679 | SCV007375793 | uncertain significance | Familial hypercholesterolemia | 2025-06-14 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 652 of the LDLR protein (p.Met652Val). This variant is present in population databases (rs730882111, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of LDLR-related conditions (PMID: 29459468, 33740630). ClinVar contains an entry for this variant (Variation ID: 183129). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt LDLR protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect LDLR function (PMID: 25647241). This variant disrupts the p.Met652 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20809525, 28964736). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003330519 | SCV004039145 | uncertain significance | not specified | 2023-08-14 | criteria provided, single submitter | clinical testing | Variant summary: LDLR c.1954A>G (p.Met652Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251460 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1954A>G has been reported in the literature in at least two individuals affected with high cholesterol (Balder_2018, Leren_2021). However, these report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. c.1954A>G has also been identified in at least two control individuals who did not have a history of myocardial infarction (Do_2015, Thormaehlen_2018), however cholesterol levels for these individuals were not provided. At least one functional study investigating protein overexpression and complementation showed no damaging effect of this variant (Thormaehlen_2018). The following publications have been ascertained in the context of this evaluation (PMID: 29459468, 25487149, 33740630, 25647241). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely benign, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| LDLR- |
RCV000237649 | SCV000295773 | likely benign | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000237649 | SCV000606562 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research | ||
| Dept. |
RCV000162006 | SCV000189581 | not provided | not provided | no classification provided | in vitro |