ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1085A>C (p.Asp362Ala) (rs138315511)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000030124 SCV000052779 likely pathogenic Familial hypercholesterolemia 1 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Cardiovascular Biomarker Research Laboratory,Mayo Clinic RCV000030124 SCV000266320 uncertain significance Familial hypercholesterolemia 1 2016-02-19 criteria provided, single submitter research MAF =<0.3%, likely pathogenic based on the integrative in-silico score, previously reported as P/LP in the literature
LDLR-LOVD, British Heart Foundation RCV000030124 SCV000295209 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000030124 SCV000484750 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Color Health, Inc RCV000775055 SCV000909155 uncertain significance Familial hypercholesterolemia 2020-12-22 criteria provided, single submitter clinical testing This missense variant (also known as p.Asp341Ala in the mature protein) replaces aspartic acid with alanine at codon 362 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 11810272, 15823288, 16542394, 27765764, 28145427). This variant has also been identified in 23/282712 chromosomes 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.
CSER _CC_NCGL, University of Washington RCV000148563 SCV000190276 likely benign Hypercholesterolaemia 2014-06-01 no assertion criteria provided research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000030124 SCV000606323 benign Familial hypercholesterolemia 1 no assertion criteria provided research
Broad Institute Rare Disease Group, Broad Institute RCV000030124 SCV001422628 uncertain significance Familial hypercholesterolemia 1 2020-01-22 no assertion criteria provided curation The p.Asp362Ala variant in LDLR has been reported in 8 individuals (including 5 Danish and 1 Dutch individuals) with Familial Hypercholesterolemia (PMID: 27765764, 11810272, 16542394, 28145427), and has been identified in 0.01782% (23/129086) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs138315511). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as a benign variant, likely benign variant, VUS, and likely pathogenic variant (Variation ID: 36452). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Moderate, PP3 (Richards 2015).

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