ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1252G>A (p.Glu418Lys)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
SNPedia RCV000210833 SCV000267119 likely pathogenic Familial hypercholesterolemia 1 2016-04-03 criteria provided, single submitter literature only
LDLR-LOVD, British Heart Foundation RCV000210833 SCV000295328 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000210833 SCV000540807 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000210833 SCV000588569 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Iberoamerican FH Network RCV000210833 SCV000748144 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Color Health, Inc RCV001181607 SCV001346786 likely pathogenic Familial hypercholesterolemia 2020-05-27 criteria provided, single submitter clinical testing This missense variant (also known as p.Glu397Lys in the mature protein) is located in the LDLR type B repeat 1 of the EGF precursor homology domain 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). This variant has been reported in at least two unrelated individuals affected with familial hypercholesterolemia (PMID: 18718593, 29292049, 32331935) and in an individual affected with coronary artery disease (PMID: 27050191). A functional study has shown a ~70% reduction in LDL binding activity in cells from a severely affected pediatric patient who was compound heterozygous for this variant and a pathogenic c.1845+2T>C variant (PMID: 18718593). This variant has been identified in 1/251204 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV001181607 SCV001422750 uncertain significance Familial hypercholesterolemia 2020-01-22 no assertion criteria provided curation The p.Glu418Lys variant in LDLR has been reported in 2 individuals (1 Japanese) with familial hypercholesterolemia (PMID: 27050191, 12417285), and has been identified in 0.0009% (1/113532) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs869320651). This variant has also been reported in ClinVar as likely pathogenic (Variation ID: 225182). 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: PP3, PS4_supporting (Richards 2015).

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