Submissions for variant NM_000527.5(LDLR):c.1720C>T (p.Arg574Cys) (rs185098634)

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238063	SCV000295611	likely pathogenic	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	RCV000238063	SCV000503397	uncertain significance	Familial hypercholesterolemia 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1, family member=1 /FH-Germany/software prediction damaging
Fundacion Hipercolesterolemia Familiar	RCV000238063	SCV000607630	uncertain significance	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Invitae	RCV000791378	SCV000752408	pathogenic	Familial hypercholesterolemia	2019-09-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 574 of the LDLR protein (p.Arg574Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs185098634, ExAC 0.02%). This variant has been reported in several individuals affected with hypercholesterolemia (PMID: 11462246, 19446849, 26892515), probable hypercholesterolemia (PMID: 23375686, 20145306), and myocardial infarction (PMID: 25487149). ClinVar contains an entry for this variant (Variation ID: 183123). 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 and their clinical significance is uncertain. Different missense substitutions at this codon (p.Arg574His, p.Arg574Ser, p.Arg574Leu) have been reported in several individuals affected with hypercholesterolemia (PMID: 28028493, 20018285, 22698793). This suggests that the arginine residue is critical for LDLR protein function. For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000161998	SCV001151665	likely pathogenic	not provided	2018-10-01	criteria provided, single submitter	clinical testing
Color	RCV000791378	SCV001349170	likely pathogenic	Familial hypercholesterolemia	2019-01-02	criteria provided, single submitter	clinical testing
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000161998	SCV000189573	not provided	not provided		no assertion provided	in vitro
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000238063	SCV000606498	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research
Broad Institute Rare Disease Group,Broad Institute	RCV000238063	SCV001423052	uncertain significance	Familial hypercholesterolemia 1	2020-01-22	no assertion criteria provided	curation	The p.Arg574Cys variant in LDLR has been reported in 14 individuals with familial hypercholesterolemia (PMID: 29290422, 25647241, 22698793, 20145306, 25487149, 23375686, 11462246, 26892515, 19446849), and has been identified in 0.006% (8/129194) European non-Finnish chromosomes. 0.004% (1/25116) European Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs185098634). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as a VUS, likely pathogenic, and pathogenic(Variation ID#: 183123). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_moderate, PM2_supporting, PP3 (Richards 2015).