ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs879255094
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
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).
All of Us Research Program, National Institutes of Health RCV000237463 SCV004835509 uncertain significance Hypercholesterolemia, familial, 1 2023-11-20 criteria provided, single submitter clinical testing This missense variant (also known as p.Thr638Asn in the mature protein) replaces threonine with asparagine at codon 659 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). An experimental functional study using LDLR-deficient CHO-ldlA7 cells has shown that this variant does not cause a significant impact on LDLR expression (PMID: 32015373). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15199436, 23833242). This variant has not been identified 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.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237463 SCV000606565 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.