ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1429G>A (p.Asp477Asn)

dbSNP: rs780316072
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237250 SCV000295426 uncertain significance Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute, Western University RCV000237250 SCV000782914 uncertain significance Hypercholesterolemia, familial, 1 2018-01-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780376 SCV000917578 uncertain significance not specified 2018-04-30 criteria provided, single submitter clinical testing Variant summary: LDLR c.1429G>A (p.Asp477Asn) results in a conservative amino acid change located in the LDLR class B repeat of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246060 control chromosomes. This frequency is not higher than expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (8.1e-06 vs 0.0013), allowing no conclusion about variant significance. c.1429G>A has been reported in the literature in one individual affected with Familial Hypercholesterolemia. This report does not provide unequivocal conclusions about an association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The British Heart Foundation/LOVD has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance based solely on literature evidence that has already been considered in the current evaluation by our laboratory. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health RCV001177032 SCV001341141 uncertain significance Familial hypercholesterolemia 2019-05-03 criteria provided, single submitter clinical testing This missense variant (also known as p.Asp456Asn in the mature protein) replaces aspartic acid with asparagine at codon 477 of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on 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. This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 16250003). This variant has been identified in 1/251116 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.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia RCV000237250 SCV001432631 uncertain significance Hypercholesterolemia, familial, 1 2019-05-13 criteria provided, single submitter research
Invitae RCV001177032 SCV003257838 pathogenic Familial hypercholesterolemia 2023-12-21 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 477 of the LDLR protein (p.Asp477Asn). This variant is present in population databases (rs780316072, gnomAD 0.006%). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 16250003, 29172679, 31345425, 35249492; Invitae). ClinVar contains an entry for this variant (Variation ID: 251838). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV003329271 SCV004036895 uncertain significance not provided 2023-08-03 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18325082, 33740630, 32041611, 35249492, 22220933, 29172679, 16250003, 31345425, 35047021)
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000237250 SCV004807780 uncertain significance Hypercholesterolemia, familial, 1 2024-03-29 criteria provided, single submitter clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237250 SCV000606421 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research
Natera, Inc. RCV001177032 SCV002086424 uncertain significance Familial hypercholesterolemia 2020-12-11 no assertion criteria provided clinical testing

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