Submissions for variant NM_000527.5(LDLR):c.1745T>C (p.Leu582Pro)

dbSNP: rs875989930

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211698	SCV000295631	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000211698	SCV000484721	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000211698	SCV000503406	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1/software prediction damaging
Color Diagnostics, LLC DBA Color Health	RCV000775075	SCV000909177	likely pathogenic	Familial hypercholesterolemia	2023-10-25	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 582 of the LDLR protein. This variant is also known as p.Leu561Pro in the mature protein. This variant alters a conserved AA1 residue in the fifth LDLR type B repeat of the EGF precursor homology domain of the LDLR protein (a.a. 572-615), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This LDLR variant has been reported in over 10 heterozygous individuals affected with familial hypercholesterolemia (PMID: 11668627, 15199436, 15576851, 17353666, 27765764, 28161202, 34037665; Color internal data; ClinVar SCV000268635.1, SCV000503406.1). This variant has also been observed in homozygous state in one individual affected with severe homozygous familial hypercholesterolemia (PMID: 36325061). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae	RCV000775075	SCV000957611	pathogenic	Familial hypercholesterolemia	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 582 of the LDLR protein (p.Leu582Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11668627, 15199436, 27765764, 28161202, 33303402). This variant is also known as L561P. ClinVar contains an entry for this variant (Variation ID: 226372). 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000775075	SCV001422865	uncertain significance	Familial hypercholesterolemia	2020-01-22	criteria provided, single submitter	curation	The p.Leu582Pro variant in LDLR has been reported in 4 European individuals with familial hypercholesterolemia (PMID: 28161202, 15199436, 11668627), and was absent from large population studies. This variant has also been reported in ClinVar as likely pathogenic (Variation ID: 226372). 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: PM2, PP3, PS4_supporting (Richards 2015).
AiLife Diagnostics, AiLife Diagnostics	RCV002223823	SCV002502853	likely pathogenic	not provided	2022-01-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399782	SCV002712185	pathogenic	Cardiovascular phenotype	2022-03-25	criteria provided, single submitter	clinical testing	The p.L582P pathogenic mutation (also known as c.1745T>C), located in coding exon 12 of the LDLR gene, results from a T to C substitution at nucleotide position 1745. The leucine at codon 582 is replaced by proline, an amino acid with similar properties. This alteration, also referred to as L561P, has been reported in multiple familial hypercholesterolemia (FH) cohorts (Leren TP et al. Semin Vasc Med. 2004;4:75-85; Taylor A et al. Clin Genet, 2010 Jun;77:572-80; Wang J et al. Arterioscler. Thromb. Vasc. Biol. 2016;36:2439-2445; Minicocci I et al. J. Pediatr. 2017;183:100-107.e3; Ambry internal data). An alteration at the same codon (p.L582F, c.1744C>T) has also been reported in association with FH (Jiang L et al. Sci Rep. 2016;6:36823). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV002223823	SCV003918325	likely pathogenic	not provided	2022-11-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(L561P); This variant is associated with the following publications: (PMID: 27765764, 15199436, 28161202, 31653860, 33087929, 32041611, 32143996, 33740630, 34037665, 33303402, 11668627)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002223823	SCV004219957	likely pathogenic	not provided	2023-08-12	criteria provided, single submitter	clinical testing	The LDLR c.1745T>C (p.Leu582Pro) variant has been reported in the published literature in a significant number of individuals with familial hypercholesterolemia (PMIDs: 36105085 (2022), 34037665 (2021), 33740630 (2021), 28161202 (2017), 27765764 (2016), 17426749 (2006), 15576851 (2005), 15199436 (2004), and 11668627 (2001)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211698	SCV000268635	pathogenic	Hypercholesterolemia, familial, 1	2012-08-07	no assertion criteria provided	clinical testing