Submissions for variant NM_000527.5(LDLR):c.2054C>T (p.Pro685Leu)

gnomAD frequency: 0.00004  dbSNP: rs28942084

Total submissions: 37

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844731	SCV000271386	pathogenic	Homozygous familial hypercholesterolemia	2015-12-21	criteria provided, single submitter	clinical testing	The p.Pro685Leu variant in LDLR, also described as p.Pro664Leu in the literature , has been reported in >40 individuals with familial hypercholesterolemia (FH), segregated with disease in >40 affected relatives from at least 4 families, and was identified in the homozygous state in at least 10 individuals with FH (Berto lini 2013, Sharifi 2016, Medeiros 2010,Rubinsztein 1992, Soutar 1989, Soutar 199 1, Thormaehlen 2015, Van Der Graaf 2011). This variant has also been reported by other clinical laboratories in Clinvar (Variation ID 3702) and was identified i n 6/126656 European chromosomes by the Genome Aggregation Database (gnomAD, http ://gnomad.broadinstitute.org; dbSNP rs28942084). However, this frequency is low enough to be consistent with the frequency of FH in the general population. In v itro functional studies provide some evidence that the p.Pro685Leu variant may i mpact protein function (Knight 1989, Rubinsztein 1992, Thormaehlen 2015). In sum mary, this variant meets criteria to be classified as pathogenic for familial hy percholesterolemia in an autosomal dominant manner based upon presence in multip le affected individuals, segregation studies, low frequency in controls and func tional evidence. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2, PS3_Supporting .
LDLR-LOVD, British Heart Foundation	RCV000003891	SCV000295846	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000003891	SCV000322997	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/200 non-FH alleles
Robarts Research Institute, Western University	RCV000003891	SCV000484689	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	RCV000003891	SCV000503454	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 25 (1 homozygote) , family members = 22 with co-segregation / previously described in association with FH/software prediction damaging
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000003891	SCV000540854	likely pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000003891	SCV000583924	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000003891	SCV000588630	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000003891	SCV000607670	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000775085	SCV000627025	pathogenic	Familial hypercholesterolemia	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 685 of the LDLR protein (p.Pro685Leu). This variant is present in population databases (rs28942084, gnomAD 0.01%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 2726768, 11031227, 12124988, 15359125, 18718593, 21382890, 23155708, 23375686, 23669246). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. This variant is also known as p.Pro664Leu. ClinVar contains an entry for this variant (Variation ID: 3702). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LDLR function (PMID: 19013141). For these reasons, this variant has been classified as Pathogenic.
Iberoamerican FH Network	RCV000003891	SCV000748105	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV000003891	SCV000894179	pathogenic	Hypercholesterolemia, familial, 1	2021-10-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000775085	SCV000909189	pathogenic	Familial hypercholesterolemia	2024-10-15	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 685 of the EGF-like repeat C in the EGF precursor homology domain of the LDLR protein. This variant is also known as p.Pro664Leu in the mature protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional assays have demonstrated that the variant protein shows defective processing, accelerated turnover, reduced cell surface expression and impaired LDLR activity (PMID: 1464748, 25647241, 2920733, 3816797). This variant has been reported in over 200 individuals affected with familial hypercholesterolemia (PMID: 7583548, 9763532, 1464748, 1493640, 15199436, 1884514, 19318025, 19446849, 20828696, 21310417, 21382890, 22390909, 23375686, 23680767, 26343872, 26892515, 33740630, 34456200, 35052492, 36422519, 37967952). It has been shown that this variant segregates with disease in multiple affected individuals across two large families (PMID: 1493640, 1830890, 2726768). This variant has been identified in 9/282638 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Pro685Ser, is considered to be disease-causing (ClinVar variation ID: 252194), suggesting that proline at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000775085	SCV001372293	pathogenic	Familial hypercholesterolemia	2020-06-10	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.2054C>T (p.Pro685Leu) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251236 control chromosomes. c.2054C>T has been extensively reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (example, Tichy_2012, Bertolini_2013, Soutar_1989, Futema_2013). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on LDL-receptor activity (example, Bertolini_2013, Bertolini_1999, Knight_1989). The most pronounced variant effect results in 10%-<30% of normal activity. Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=9)/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000003891	SCV001432556	pathogenic	Hypercholesterolemia, familial, 1	2019-01-21	criteria provided, single submitter	research
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000003891	SCV001653656	pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000162007	SCV001715497	pathogenic	not provided	2023-02-09	criteria provided, single submitter	clinical testing	PP1_strong, PP3, PP4, PM1, PS3
GeneDx	RCV000162007	SCV001872734	pathogenic	not provided	2022-05-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate that this variant disrupts LDL receptor activity and inhibits LDL-uptake in cells (King-Underwood et al., 1991; Rubinsztein et al., 1992; Tada et al., 2009; Thormaehlen et al., 2015); Also known as P664L and FH Gujerat/Frosinone-1/Kanazawa-2; This variant is associated with the following publications: (PMID: 17142622, 19446849, 11031227, 30592178, 31447099, 1884514, 7583548, 2726768, 1830890, 1464748, 1493640, 9254862, 9763532, 17347910, 20828696, 21382890, 21310417, 22390909, 23155708, 23680767, 24529145, 25647241, 25487149, 26892515, 27831900, 24507775, 28965616, 30526649, 30112042, 30971288, 19013141, 23669246, 31491741, 34040191, 34570182, 32977124, 32041611, 32770674, 32331935, 33740630, 34037665, 33087929, 27535533, 26582918, 23375686)
Revvity Omics, Revvity	RCV000003891	SCV002017129	pathogenic	Hypercholesterolemia, familial, 1	2022-04-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000162007	SCV002046456	pathogenic	not provided	2020-12-23	criteria provided, single submitter	clinical testing	This variant has been reported in individuals affected with homozygous or heterozygous familial hypercholesterolemia in the published literature (PMID: 26892515 (2016), 26343872 (2015), 22698793 (2012), 18718593 (2009), 12417285 (2002), 9763532 (1998), 1830890 (1991), 2726768 (1989)). Additionally, functional studies indicate that this variant is damaging to LDL receptor function (PMID: 25647241 (2015), 19013141 (2009), 18718593 (2009)). This variant has also been reported to segregate with hypercholesterolemia in multiple families (PMID: 23155708 (2012), 18718593 (2009), 2726768 (1989)). Therefore, the variant is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000162007	SCV002546065	pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	LDLR: PM1, PM5, PS3:Moderate, PS4:Moderate, PM2:Supporting, PP1, PP4
Ambry Genetics	RCV002415395	SCV002728264	pathogenic	Cardiovascular phenotype	2024-10-27	criteria provided, single submitter	clinical testing	The p.P685L pathogenic mutation (also known as c.2054C>T), located in coding exon 14 of the LDLR gene, results from a C to T substitution at nucleotide position 2054. The proline at codon 685 is replaced by leucine, an amino acid with similar properties. This alteration (also referred to as p.P664L) has been described in multiple individuals with familial hypercholesterolemia including homozygous and compound heterozygous cases, and has been reported to segregate with disease in several families (Soutar AK et al. Proc Natl Acad Sci USA. 1989;86:4166-70; King-Underwood L et al. Clin Genet. 1991;40:17-28; Defesche JC et al. Clin Genet. 1992;42:273-80; Maruyama T et al. Arterioscler Thromb Vasc Biol. 1995;15:1713-8; Mak YT et al. Arterioscler Thromb Vasc Biol. 1998;18:1600-5; Leren TP et al. Semin Vasc Med. 2004;4:75-85; Alonso R et al. Clin. Biochem. 2009;42:899-903; Guardamagna O et al. J Pediatr. 2009;155:199-204.e2; Medeiros AM et al. Atherosclerosis. 2010;212:553-8; Shin DG et al. Atherosclerosis. 2015;243:53-8). This alteration has been reported to result in defective LDLR activity in studies of patient derived cells (Knight BL et al. Eur J Biochem. 1989;179:693-8; King-Underwood L et al. Clin Genet. 1991;40:17-28; Tada H et al. Clin. Chim Acta. 2009;400:42-7). This amino acid position is highly conserved in available vertebrate species. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000162007	SCV003799235	pathogenic	not provided	2022-11-29	criteria provided, single submitter	clinical testing	The LDLR c.2054C>T; p.Pro685Leu variant (rs28942084), also known as P664L, is reported in numerous individuals affected with homozygous or heterozygous familial hypercholesterolemia, and shown to segregate with hypercholesterolemia in multiple families (Cheng 2018, Lee 2019, Miyake 2009, Pandey 2016, Sharifi 2016, Soutar 1989, Sturm 2021). This variant is also reported in ClinVar (Variation ID: 3702). Furthermore, functional analyses demonstrate an affect of this variant on protein function (Rubinsztein 1992, Tada 2009, Thormaehlen 2015). This variant is found in the general population with an overall allele frequency of 0.003% (9/282638 alleles) in the Genome Aggregation Database. The proline at codon 685 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.883). Based on available information, this variant is considered to be pathogenic. References: Cheng X et al. Novel compound heterozygous mutations in low density lipoprotein receptor gene causes a severe phenotype in a Chinese hypercholesterolemia family. Exp Ther Med. 2018 Aug;16(2):901-907. PMID: 30112042. Lee C et al. Effects of familial hypercholesterolemia-associated genes on the phenotype of premature myocardial infarction. Lipids Health Dis. 2019 Apr 11;18(1):95. PMID: 30971288. Miyake Y et al. Update of Japanese common LDLR gene mutations and their phenotypes: Mild type mutation L547V might predominate in the Japanese population. Atherosclerosis. 2009 Mar;203(1):153-60. PMID: 18718593. Pandey S et al. Cascade Screening for Familial Hypercholesterolemia: PCR Methods with Melting-Curve Genotyping for the Targeted Molecular Detection of Apolipoprotein B and LDL Receptor Gene Mutations to Identify Affected Relatives. J Appl Lab Med. 2016 Sep 1;1(2):109-118. PMID: 33626794. Rubinsztein DC et al. Identification and properties of the proline664-leucine mutant LDL receptor in South Africans of Indian origin. J Lipid Res. 1992 Nov;33(11):1647-55. PMID: 1464748. Sharifi M et al. The genetic spectrum of familial hypercholesterolemia in south-eastern Poland. Metabolism. 2016 Mar;65(3):48-53. PMID: 26892515. Soutar AK et al. Identification of a point mutation in growth factor repeat C of the low density lipoprotein-receptor gene in a patient with homozygous familial hypercholesterolemia that affects ligand binding and intracellular movement of receptors. Proc Natl Acad Sci U S A. 1989 Jun;86(11):4166-70. PMID: 2726768. Sturm AC et al. Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis. JAMA Cardiol. 2021 Aug 1;6(8):902-909. PMID: 34037665. Tada H et al. A novel method for determining functional LDL receptor activity in familial hypercholesterolemia: application of the CD3/CD28 assay in lymphocytes. Clin Chim Acta. 2009 Feb;400(1-2):42-7. PMID: 19013141. Thormaehlen AS et al. Systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction. PLoS Genet. 2015 Feb 3;11(2):e1004855. PMID: 25647241.
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000775085	SCV004123054	pathogenic	Familial hypercholesterolemia	2023-07-01	criteria provided, single submitter	research
All of Us Research Program, National Institutes of Health	RCV000003891	SCV004818488	pathogenic	Hypercholesterolemia, familial, 1	2024-08-29	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 685 of the EGF-like repeat C in the EGF precursor homology domain of the LDLR protein. This variant is also known as p.Pro664Leu in the mature protein. 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). Functional assays have demonstrated that the variant protein shows defective processing, accelerated turnover, reduced cell surface expression and impaired LDLR activity (PMID: 1464748, 25647241, 2920733, 3816797). This variant has been reported in over 200 individuals affected with familial hypercholesterolemia (PMID: 7583548, 9763532, 1464748, 1493640, 15199436, 1884514, 19318025, 19446849, 20828696, 21310417, 21382890, 22390909, 23375686, 23680767, 26343872, 26892515, 33740630, 34456200, 35052492, 36422519). It has been shown that this variant segregates with disease in multiple affected individuals across two large families (PMID: 1493640, 1830890, 2726768). This variant has been identified in 9/282638 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Pro685Ser, is considered to be disease-causing (ClinVar variation ID: 252194), suggesting that proline at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000775085	SCV005045754	pathogenic	Familial hypercholesterolemia	2021-04-27	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000162007	SCV005198663	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000003891	SCV005416698	pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing	PM2_Supporting+PM3+PS4+PP1_Strong+PS3_Supporting
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV005403716	SCV006067646	pathogenic	Dyslipidemia	2025-01-29	criteria provided, single submitter	clinical testing	PS3, PS4, PM5_strong, PP1_strong, PM2, PM3, PP3, PP4
OMIM	RCV000003891	SCV000024056	pathogenic	Hypercholesterolemia, familial, 1	1992-12-01	no assertion criteria provided	literature only
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000162007	SCV000189582	not provided	not provided		no assertion provided	in vitro
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000003891	SCV000268656	pathogenic	Hypercholesterolemia, familial, 1	2010-04-13	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000003891	SCV000606588	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000162007	SCV001740637	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000162007	SCV001919668	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000775085	SCV002086862	pathogenic	Familial hypercholesterolemia	2021-02-19	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004745144	SCV005348165	pathogenic	LDLR-related disorder	2024-08-28	no assertion criteria provided	clinical testing	The LDLR c.2054C>T variant is predicted to result in the amino acid substitution p.Pro685Leu. This variant has been repeatedly reported to be causative for hypercholesterolemia (see for example at Bertolini et al. 2013. PubMed ID: 23375686; Hori et al. 2019. PubMed ID: 31491741; Gratton et al. 2023. PubMed ID: 37409534). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic or likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/3702/). This variant is interpreted as pathogenic.