ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2252G>A (p.Arg751Gln) (rs200142970)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER _CC_NCGL, University of Washington RCV000148593 SCV000190308 uncertain significance Hypercholesterolaemia 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Cardiovascular Biomarker Research Laboratory,Mayo Clinic RCV000210245 SCV000266313 uncertain significance Familial hypercholesterolemia 1 2015-08-31 criteria provided, single submitter research MAF =<0.3%, LDL-C >=160 mg/dL
LDLR-LOVD, British Heart Foundation RCV000210245 SCV000295926 likely benign Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Invitae RCV000815637 SCV000956098 uncertain significance Familial hypercholesterolemia 2018-09-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 751 of the LDLR protein (p.Arg751Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs200142970, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 16250003, 16159606). ClinVar contains an entry for this variant (Variation ID: 161286). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000996761 SCV001151674 uncertain significance not provided 2018-07-01 criteria provided, single submitter clinical testing
Color RCV000815637 SCV001344869 uncertain significance Familial hypercholesterolemia 2020-01-15 criteria provided, single submitter clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000210245 SCV000606620 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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