ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1955T>C (p.Met652Thr) (rs875989936)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211590 SCV000295774 uncertain significance Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000211590 SCV000503437 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 2 / Other mutation at same codon/Software predictions: Conflicting
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000211590 SCV000583911 likely pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Invitae RCV000775082 SCV000627024 likely pathogenic Familial hypercholesterolemia 2019-02-06 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 652 of the LDLR protein (p.Met652Thr). The methionine residue is weakly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several unrelated individuals affected with hypercholesterolemia (PMID: 20236128, 20809525, Invitae). ClinVar contains an entry for this variant (Variation ID: 226382). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color RCV000775082 SCV000909186 uncertain significance Familial hypercholesterolemia 2020-03-26 criteria provided, single submitter clinical testing
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211590 SCV000268651 pathogenic Familial hypercholesterolemia 1 2008-06-25 no assertion criteria provided clinical testing

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