ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.681C>A (p.Asp227Glu)

dbSNP: rs121908028
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation RCV000455843 SCV000540751 pathogenic Hypercholesterolemia, familial, 1 2016-11-05 criteria provided, single submitter clinical testing Disrupt SDE motif. SDE bind structural Ca2+.
GeneDx RCV002248667 SCV002520220 likely pathogenic not provided 2022-05-19 criteria provided, single submitter clinical testing Also known as p.D206E and FH-Afrikans; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11491306, 7682459, 27680772, 29128982, 28502495, 18718593, 31491741, 32331935, 17087781)
Ambry Genetics RCV002365580 SCV002664174 pathogenic Cardiovascular phenotype 2021-05-26 criteria provided, single submitter clinical testing The p.D227E pathogenic mutation (also known as c.681C>A), located in coding exon 4 of the LDLR gene, results from a C to A substitution at nucleotide position 681. The aspartic acid at codon 227 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration, which is also known as p.D206E, has been reported in familial hypercholesterolemia (FH) cohorts in both the heterozygous and homozygous states (Charng MJ et al. Eur J Clin Invest, 2006 Dec;36:866-74; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4; Reiman A et al. Ann Clin Biochem, 2016 Nov;53:654-662; Hori M et al. Atherosclerosis, 2019 10;289:101-108). In addition, a different alteration located at the same position, resulting in the same protein change, c.681C>G (p.D227E), is a founder mutation that accounts for the majority of FH in the Afrikaner population (Leitersdorf et al. J Clin Invest.1989;84(3):954-61; King et al. N Z Med J. 2010;123(1319):79-82) and had also been reported in affected individuals of multiple ethnicities (Gudnason et al. Arterioscler. Thromb. 1993;13(1):56-63; Leren et al. Semin Vasc Med. 2004;4(1):75-85; Bertolini et al Atherosclerosis 2013;227(2):342-348; Sharifi et al. Metab. Clin. Exp. 2016;65(3):48-53). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Revvity Omics, Revvity RCV000455843 SCV003827806 pathogenic Hypercholesterolemia, familial, 1 2022-10-26 criteria provided, single submitter clinical testing
Invitae RCV003581665 SCV004298331 pathogenic Familial hypercholesterolemia 2023-11-01 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 227 of the LDLR protein (p.Asp227Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 2352257, 2569482, 17087781, 17539906, 19467224, 21310417, 21382890, 22883975, 31491741). This variant is also known as Asp206Glu. ClinVar contains an entry for this variant (Variation ID: 403632). 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.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000455843 SCV000606197 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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