ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1057G>A (p.Glu353Lys)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237927 SCV000295172 uncertain significance Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000237927 SCV000588545 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Invitae RCV000775052 SCV000821458 uncertain significance Familial hypercholesterolemia 2022-09-13 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 353 of the LDLR protein (p.Glu353Lys). This variant is present in population databases (rs370471092, gnomAD 0.03%). This missense change has been observed in individual(s) with familial hypercholesterolemia and myocardial infarction (PMID: 11810272, 15823288, 20506408, 25647241, 27828139, 27878139, 30971288). This variant is also known as p.Glu332Lys. ClinVar contains an entry for this variant (Variation ID: 161275). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (PMID: 25647241). 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.
Color Diagnostics, LLC DBA Color Health RCV000775052 SCV000909152 uncertain significance Familial hypercholesterolemia 2023-11-16 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 353 of the LDLR protein. This variant is also known as p.Glu332Lys in the mature protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. A functional study using transfected HeLa cells has shown inconclusive results regarding this variant's impact on LDLR expression (PMID: 25647241). This variant has been reported in four individuals affected with familial hypercholesterolemia (PMID: 11810272, 15823288, 20506408, 33994402, 34998859), as well as in one individual affected with premature myocardial infarction (PMID: 30971288). This variant has been identified in 16/281978 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.
Ambry Genetics RCV002399518 SCV002713861 uncertain significance Cardiovascular phenotype 2023-12-22 criteria provided, single submitter clinical testing The c.1057G>A (p.E353K) alteration is located in exon 7 (coding exon 7) of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 1057, causing the glutamic acid (E) at amino acid position 353 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV000237927 SCV002784200 uncertain significance Hypercholesterolemia, familial, 1 2021-11-21 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000237927 SCV004820261 uncertain significance Hypercholesterolemia, familial, 1 2024-01-11 criteria provided, single submitter clinical testing This missense variant (also known as p.Glu332Lys in the mature protein) replaces glutamic acid with lysine at codon 353 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 11810272, 15823288, 20506408; Huang et al, 2021, doi.org/10.5551/jat.62773), as well as in an individual affected with premature myocardial infarction (PMID: 30971288). This variant has also been identified in 16/281978 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.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161978 SCV000189553 not provided not provided no assertion provided in vitro
CSER _CC_NCGL, University of Washington RCV002051668 SCV000190295 uncertain significance Hypercholesterolemia 2014-06-01 no assertion criteria provided research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237927 SCV000606304 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research
Natera, Inc. RCV000775052 SCV001460265 uncertain significance Familial hypercholesterolemia 2020-09-16 no assertion criteria provided clinical testing

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