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

Total submissions: 7

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	2019-01-29	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 Health, Inc	RCV000775082	SCV000909186	uncertain significance	Familial hypercholesterolemia	2020-03-26	criteria provided, single submitter	clinical testing
Laboratory of Molecular Genetics,National Medical Research Center for Therapy and Preventive Medicine	RCV000775082	SCV001482447	uncertain significance	Familial hypercholesterolemia		criteria provided, single submitter	research
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