ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1976C>A (p.Thr659Asn)

gnomAD frequency: 0.00001  dbSNP: rs879255094
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel 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-LOVD, British Heart Foundation 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, Academisch Medisch Centrum RCV000237463 SCV000606565 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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