Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000237463 | SCV004022387 | uncertain significance | Hypercholesterolemia, familial, 1 | 2023-03-20 | reviewed by expert panel | curation | The NM_000527.5(LDLR):c.1976C>A (p.Thr659Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, BS3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00002413 (0.002413%) in African/African American genomes (gnomAD v3.1.2). BS3 - Level 1 assays: PMID 32015373: Heterologous cells, FACS assays - result - 96% cell surface LDLR, 99% LDL-LDLR binding and 97% uptake. ---- functional study is consistent with no damaging effect. |
LDLR- |
RCV000237463 | SCV000295787 | likely benign | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Invitae | RCV002518491 | SCV003443107 | uncertain significance | Familial hypercholesterolemia | 2022-08-09 | criteria provided, single submitter | clinical testing | 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. Experimental studies have shown that this missense change does not substantially affect LDLR function (PMID: 2015373). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 252141). This missense change has been observed in individual(s) with LDLR-related conditions (PMID: 15199436, 23833242). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 659 of the LDLR protein (p.Thr659Asn). |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000237463 | SCV000606565 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |