0/200 non-FH alleles
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.2054C>T (p.Pro685Leu)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(35)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
35
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000527.5(LDLR):c.2054C>T (p.Pro685Leu)
Variation ID: 3702 Accession: VCV000003702.70
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.2 19: 11120436 (GRCh38) [ NCBI UCSC ] 19: 11231112 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Oct 20, 2024 Mar 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.2054C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Pro685Leu missense NM_001195798.2:c.2054C>T NP_001182727.1:p.Pro685Leu missense NM_001195799.2:c.1931C>T NP_001182728.1:p.Pro644Leu missense NM_001195800.2:c.1550C>T NP_001182729.1:p.Pro517Leu missense NM_001195803.2:c.1606+203C>T intron variant NC_000019.10:g.11120436C>T NC_000019.9:g.11231112C>T NG_009060.1:g.36056C>T LRG_274:g.36056C>T LRG_274t1:c.2054C>T LRG_274p1:p.Pro685Leu P01130:p.Pro685Leu - Protein change
- P685L, P517L, P644L
- Other names
-
P664L
FH Zambia
FH Gujerat
FH Frosinone1
FH Kanazawa-2
FH Frosinone-1
NP_000518.1:p.P685L
- Canonical SPDI
- NC_000019.10:11120435:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
functional variant; Sequence Ontology [ SO:0001536]disruptive missense [submitted by Dept. of Genetics and Pharmacogenomics, Merck Research Labs]
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| LDLR | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4076 | 4352 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (17) |
criteria provided, multiple submitters, no conflicts
|
Jan 5, 2024 | RCV000003891.35 | |
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Jan 17, 2024 | RCV000775085.17 | |
| Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
Mar 1, 2024 | RCV000162007.38 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 30, 2023 | RCV002415395.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 21, 2015 | RCV000844731.5 | |
|
LDLR-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Aug 28, 2024 | RCV004745144.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Likely pathogenic
(Mar 25, 2016)
|
criteria provided, single submitter
Method: literature only
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
LDLR-LOVD, British Heart Foundation
Accession: SCV000295846.2
First in ClinVar: Jul 29, 2016 Last updated: Mar 31, 2019 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
Observation 3:
Number of individuals with the variant: 1
Observation 4:
Number of individuals with the variant: 1
Observation 5:
Number of individuals with the variant: 1
Observation 6:
Number of individuals with the variant: 1
Observation 7:
Number of individuals with the variant: 1
Observation 8:
Number of individuals with the variant: 1
Observation 9:
Number of individuals with the variant: 1
Observation 10:
Number of individuals with the variant: 1
Observation 11:
Number of individuals with the variant: 1
Observation 12:
Number of individuals with the variant: 1
|
|
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Pathogenic
(Mar 01, 2016)
|
criteria provided, single submitter
Method: research
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
Accession: SCV000322997.1
First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016 |
Comment:
0/200 non-FH alleles
Observation 1:
Comment on evidence:
%MAF (ExAC):0.006605
Observation 2:
Comment on evidence:
Homozygous patient fibroblast, 125I-LDL assays / 125I-LDL and RNA assays
Result:
15-30% /20-25% LDLR activity
|
|
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Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Robarts Research Institute, Western University
Accession: SCV000484689.1
First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016 |
Number of individuals with the variant: 2
|
|
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Likely pathogenic
(Dec 16, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix
Accession: SCV000503454.1
First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016 |
Comment:
subjects mutated among 2600 FH index cases screened = 25 (1 homozygote) , family members = 22 with co-segregation / previously described in association with … (more)
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 (less)
Number of individuals with the variant: 25
|
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Likely pathogenic
(Nov 05, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
inherited
|
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation
Additional submitter:
Centre of Molecular Biology and Gene Therapy, University Hospital Brno
Accession: SCV000540854.1
First in ClinVar: Apr 08, 2017 Last updated: Apr 08, 2017 |
Number of individuals with the variant: 5
Clinical Features:
Hypercholesterolemia (present) , Xanthelasma (present) , Tendon xanthoma (present) , Corneal arcus (present) , Ischemic stroke (present)
Family history: yes
Age: 29-66 years
Sex: mixed
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Tissue: Whole blood
|
|
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Pathogenic
(Mar 30, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Hypercholesterolemia
Affected status: yes
Allele origin:
germline
|
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille
Accession: SCV000583924.1
First in ClinVar: Apr 08, 2017 Last updated: Apr 08, 2017
Comment:
ACMG Guidelines: Pathogenic (ii)
|
Number of individuals with the variant: 39
Clinical Features:
Hyperbetalipoproteinemia (present) , Hypercholesterolemia (present)
Indication for testing: Familial Hypercholesterolemia
Sex: mixed
Geographic origin: France
Comment on evidence:
Dutch Lipid Clinic Scoring : Definite FH
Secondary finding: no
|
|
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Pathogenic
(Mar 01, 2016)
|
criteria provided, single submitter
Method: research
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Study: HipercolBrasil
Accession: SCV000588630.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017 |
Observation 1:
Comment on evidence:
%MAF(ExAC):0.006605
Observation 2:
Comment on evidence:
Assay description:Hmz patient fibroblast, 125I-LDL assays / 125I-LDL and RNA assays
Result:
20-25% / 15-30% LDLR activity
|
|
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Pathogenic
(Dec 21, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Homozygous familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000271386.3
First in ClinVar: May 29, 2016 Last updated: Aug 31, 2019 |
Comment:
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 … (more)
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 . (less)
Number of individuals with the variant: 2
|
|
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Pathogenic
(Jun 10, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001372293.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jan 21, 2019)
|
criteria provided, single submitter
Method: research
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia
Accession: SCV001432556.1
First in ClinVar: Sep 19, 2020 Last updated: Sep 19, 2020 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
Observation 3:
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
|
|
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Pathogenic
(Oct 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894179.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
|
|
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Pathogenic
(Nov 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV003799235.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(May 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001872734.3
First in ClinVar: Sep 19, 2021 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Dec 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002046456.2
First in ClinVar: Jan 01, 2022 Last updated: Jan 06, 2024 |
Comment:
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), … (more)
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. (less)
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|
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Pathogenic
(Apr 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002017129.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
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Pathogenic
(Jan 17, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000627025.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
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). … (more)
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. This variant is also known as p.Pro664Leu. ClinVar contains an entry for this variant (Variation ID: 3702). 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%. Experimental studies have shown that this missense change affects LDLR function (PMID: 19013141). For these reasons, this variant has been classified as Pathogenic. (less)
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|
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Pathogenic
(Oct 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000909189.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
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. … (more)
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. (less)
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|
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Pathogenic
(Jan 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004818488.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
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. … (more)
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. (less)
Number of individuals with the variant: 2
|
|
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Pathogenic
(Apr 27, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
familial hypercholesterolemia
Affected status: unknown
Allele origin:
unknown
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV005045754.1
First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024 |
|
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Pathogenic
(Jul 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198663.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
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Pathogenic
(Mar 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002546065.16
First in ClinVar: Jul 09, 2022 Last updated: Oct 20, 2024 |
Comment:
LDLR: PM1, PM5, PS3:Moderate, PS4:Moderate, PM2:Supporting, PP1, PP4
Number of individuals with the variant: 2
|
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Pathogenic
(Mar 01, 2016)
|
criteria provided, single submitter
Method: research
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Fundacion Hipercolesterolemia Familiar
Study: SAFEHEART
Accession: SCV000607670.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
Observation 1:
Comment on evidence:
%MAF(ExAC):0.006605
Observation 2:
Comment on evidence:
Hmz patient fibroblast, 125I-LDL assays / 125I-LDL and RNA assays
Result:
20-25% / 15-30% LDLR activity
|
|
|
Pathogenic
(Mar 01, 2016)
|
criteria provided, single submitter
Method: research
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Iberoamerican FH Network
Accession: SCV000748105.1
First in ClinVar: May 19, 2018 Last updated: May 19, 2018
Comment:
Variant present in the database from Argentina
|
Observation 1:
Comment on evidence:
%MAF(ExAC):0.006605
Observation 2:
Comment on evidence:
Assay Description:Hmz patient fibroblast, 125I-LDL assays / 125I-LDL and RNA assays
Result:
20-25% / 15-30% LDLR activity
|
|
|
Pathogenic
(May 24, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II
Accession: SCV001653656.1
First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021 |
Number of individuals with the variant: 9
Ethnicity/Population group: Caucasian
Geographic origin: Italy
|
|
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Pathogenic
(Jul 01, 2023)
|
criteria provided, single submitter
Method: research
|
Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
|
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand
Accession: SCV004123054.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
|
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Pathogenic
(Feb 09, 2023)
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criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001715497.3
First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024 |
Comment:
PP1_strong, PP3, PP4, PM1, PS3
Number of individuals with the variant: 3
|
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Pathogenic
(Jun 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002728264.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.2054C>T (p.P685L) alteration is located in exon 14 (coding exon 14) of the LDLR gene. This alteration results from a C to T substitution … (more)
The c.2054C>T (p.P685L) alteration is located in exon 14 (coding exon 14) of the LDLR gene. This alteration results from a C to T substitution at nucleotide position 2054, causing the proline (P) at amino acid position 685 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.003% (9/282638) total alleles studied. The highest observed frequency was 0.012% (3/24966) of African alleles. This alteration (also referred to as p.P664L) has been described in multiple individuals with familial hypercholesterolemia from varying ethnic backgrounds, including homozygous and compound heterozygous cases, and has been reported to segregate with disease in several families (Soutar, 1989; King-Underwood, 1991; Defesche, 1992; Maruyama, 1995; Mak, 1998; Leren, 2004; Alonso, 2009; Guardamagna, 2009; Medeiros, 2010; Shin, 2015). This amino acid position is highly conserved in available vertebrate species. This alteration has been reported to result in defective LDLR activity in studies of patient derived cells (Knight, 1989; King-Underwood, 1991; Tada, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
|
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Pathogenic
(Dec 01, 1992)
|
no assertion criteria provided
Method: literature only
|
FH ZAMBIA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000024056.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 23, 2019 |
Comment on evidence:
In an Asiatic Indian with FHCL1 (143890), Knight et al. (1989) and Soutar et al. (1989) found a CCG-to-CTG mutation changing proline-664 to leucine. Knight … (more)
In an Asiatic Indian with FHCL1 (143890), Knight et al. (1989) and Soutar et al. (1989) found a CCG-to-CTG mutation changing proline-664 to leucine. Knight et al. (1989) found that the precursor form of the mutant receptor is converted more slowly than normal, and the mature form on the cell surface binds LDL less well than normal. Soutar et al. (1991) identified this mutation in a large Asian-Indian kindred containing 22 heterozygotes and 3 homozygotes. All the heterozygotes had a raised level of plasma total cholesterol and low density lipoprotein cholesterol, but were remarkably free from premature coronary disease. No correlation could be found between the apo(a) phenotype (152200) and the presence or absence of the LDLR mutation. There was, however, evidence for an inherited trait that markedly increased Lp(a) concentration, which did not segregate with either apo(a) or the defective LDLR allele. FH Zambia was found in a patient with familial hypercholesterolemia who was of Indian origin residing in Zambia. Rubinsztein et al. (1992) found the same mutation in 4 South African families of Muslim religion who traced their origin to the vicinity of Surat in the Gujerat province of India. Functional studies suggested that the FH in these subjects was due to low steady-state levels of receptor molecules that are functionally normal but exhibit accelerated turnover. Among 915 consecutive patients with FH and of Dutch descent, Defesche et al. (1992) found 7 persons with the C-to-T transition at nucleotide 2054 in exon 14. All the patients shared the same haplotype. Contrary to previous reports, no difference was found in plasma levels of Lp(a) between family members with the mutation in exon 14 and unaffected persons. (less)
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001740637.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001919668.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
|
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Pathogenic
(Feb 19, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002086862.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
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Pathogenic
(Aug 28, 2024)
|
no assertion criteria provided
Method: clinical testing
|
LDLR-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005348165.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Apr 13, 2010)
|
no assertion criteria provided
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
|
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital
Accession: SCV000268656.1
First in ClinVar: May 21, 2016 Last updated: May 21, 2016 |
Number of individuals with the variant: 6
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Accession: SCV000606588.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
|
|
not provided
(-)
|
no classification provided
(in vitro)
Method: in vitro
|
not provided
Affected status: not applicable
Allele origin:
not applicable
|
Dept. of Genetics and Pharmacogenomics, Merck Research Labs
Accession: SCV000189582.1
First in ClinVar: Feb 28, 2015 Last updated: Feb 28, 2015
Comment:
In vitro functional profiling of LDL-receptor missense alleles identified through large-scale association testing
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Comment:
Comment:
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
Comment:
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 .
Comment:
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.
Comment:
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.
Comment:
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)
Comment:
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.
Comment:
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. This variant is also known as p.Pro664Leu. ClinVar contains an entry for this variant (Variation ID: 3702). 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%. Experimental studies have shown that this missense change affects LDLR function (PMID: 19013141). For these reasons, this variant has been classified as Pathogenic.
Comment:
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.
Comment:
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.
Comment:
LDLR: PM1, PM5, PS3:Moderate, PS4:Moderate, PM2:Supporting, PP1, PP4
Comment:
PP1_strong, PP3, PP4, PM1, PS3
Comment:
The c.2054C>T (p.P685L) alteration is located in exon 14 (coding exon 14) of the LDLR gene. This alteration results from a C to T substitution at nucleotide position 2054, causing the proline (P) at amino acid position 685 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.003% (9/282638) total alleles studied. The highest observed frequency was 0.012% (3/24966) of African alleles. This alteration (also referred to as p.P664L) has been described in multiple individuals with familial hypercholesterolemia from varying ethnic backgrounds, including homozygous and compound heterozygous cases, and has been reported to segregate with disease in several families (Soutar, 1989; King-Underwood, 1991; Defesche, 1992; Maruyama, 1995; Mak, 1998; Leren, 2004; Alonso, 2009; Guardamagna, 2009; Medeiros, 2010; Shin, 2015). This amino acid position is highly conserved in available vertebrate species. This alteration has been reported to result in defective LDLR activity in studies of patient derived cells (Knight, 1989; King-Underwood, 1991; Tada, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Comment:
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.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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has functional consequence
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Dept. of Genetics and Pharmacogenomics, Merck Research Labs
Accession: SCV000189582.1
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Comment:
disruptive missense
|
Comment:
0/200 non-FH alleles
Comment:
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
Comment:
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 .
Comment:
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.
Comment:
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.
Comment:
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)
Comment:
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.
Comment:
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. This variant is also known as p.Pro664Leu. ClinVar contains an entry for this variant (Variation ID: 3702). 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%. Experimental studies have shown that this missense change affects LDLR function (PMID: 19013141). For these reasons, this variant has been classified as Pathogenic.
Comment:
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.
Comment:
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.
Comment:
LDLR: PM1, PM5, PS3:Moderate, PS4:Moderate, PM2:Supporting, PP1, PP4
Comment:
PP1_strong, PP3, PP4, PM1, PS3
Comment:
The c.2054C>T (p.P685L) alteration is located in exon 14 (coding exon 14) of the LDLR gene. This alteration results from a C to T substitution at nucleotide position 2054, causing the proline (P) at amino acid position 685 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.003% (9/282638) total alleles studied. The highest observed frequency was 0.012% (3/24966) of African alleles. This alteration (also referred to as p.P664L) has been described in multiple individuals with familial hypercholesterolemia from varying ethnic backgrounds, including homozygous and compound heterozygous cases, and has been reported to segregate with disease in several families (Soutar, 1989; King-Underwood, 1991; Defesche, 1992; Maruyama, 1995; Mak, 1998; Leren, 2004; Alonso, 2009; Guardamagna, 2009; Medeiros, 2010; Shin, 2015). This amino acid position is highly conserved in available vertebrate species. This alteration has been reported to result in defective LDLR activity in studies of patient derived cells (Knight, 1989; King-Underwood, 1991; Tada, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Long-Term Efficacy and Safety of Evinacumab in Patients with Homozygous Familial Hypercholesterolemia: Real-World Clinical Experience. | Stefanutti C | Pharmaceuticals (Basel, Switzerland) | 2022 | PMID: 36422519 |
| Establishing the Mutational Spectrum of Hungarian Patients with Familial Hypercholesterolemia. | Madar L | Genes | 2022 | PMID: 35052492 |
| Phenotypic and Genetic Analyses of Korean Patients with Familial Hypercholesterolemia: Results from the KFH Registry 2020. | Kim H | Journal of atherosclerosis and thrombosis | 2022 | PMID: 34456200 |
| Effect of Whole-Genome Sequencing on the Clinical Management of Acutely Ill Infants With Suspected Genetic Disease: A Randomized Clinical Trial. | NICUSeq Study Group | JAMA pediatrics | 2021 | PMID: 34570182 |
| A randomized controlled trial of genetic testing and cascade screening in familial hypercholesterolemia. | Ajufo E | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 34040191 |
| Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis. | Sturm AC | JAMA cardiology | 2021 | PMID: 34037665 |
| Molecular genetic testing for autosomal dominant hypercholesterolemia in 29,449 Norwegian index patients and 14,230 relatives during the years 1993-2020. | Leren TP | Atherosclerosis | 2021 | PMID: 33740630 |
| Exome sequencing and characterization of 49,960 individuals in the UK Biobank. | Van Hout CV | Nature | 2020 | PMID: 33087929 |
| Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features. | Bertolini S | Atherosclerosis | 2020 | PMID: 32977124 |
| Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia. | Rieck L | Clinical genetics | 2020 | PMID: 32770674 |
| A catalog of the pathogenic mutations of LDL receptor gene in Japanese familial hypercholesterolemia. | Tada H | Journal of clinical lipidology | 2020 | PMID: 32331935 |
| Six years' experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias. | Dron JS | BMC medical genomics | 2020 | PMID: 32041611 |
| Impact of LDLR and PCSK9 pathogenic variants in Japanese heterozygous familial hypercholesterolemia patients. | Hori M | Atherosclerosis | 2019 | PMID: 31491741 |
| Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: agibbs@bcm.edu | American journal of human genetics | 2019 | PMID: 31447099 |
| Effects of familial hypercholesterolemia-associated genes on the phenotype of premature myocardial infarction. | Lee C | Lipids in health and disease | 2019 | PMID: 30971288 |
| Lipid profile and genetic status in a familial hypercholesterolemia pediatric population: exploring the LDL/HDL ratio. | Di Taranto MD | Clinical chemistry and laboratory medicine | 2019 | PMID: 30710474 |
| Genetic variations in familial hypercholesterolemia and cascade screening in East Asians. | Chan ML | Molecular genetics & genomic medicine | 2019 | PMID: 30592178 |
| Application of expanded genetic analysis in the diagnosis of familial hypercholesterolemia in patients with very early-onset coronary artery disease. | Cao YX | Journal of translational medicine | 2018 | PMID: 30526649 |
| Novel compound heterozygous mutations in low density lipoprotein receptor gene causes a severe phenotype in a Chinese hypercholesterolemia family. | Cheng X | Experimental and therapeutic medicine | 2018 | PMID: 30112042 |
| Spectrum of mutations in Italian patients with familial hypercholesterolemia: New results from the LIPIGEN study. | Pirillo A | Atherosclerosis. Supplements | 2017 | PMID: 28965616 |
| Aggregate penetrance of genomic variants for actionable disorders in European and African Americans. | Natarajan P | Science translational medicine | 2016 | PMID: 27831900 |
| The genetic spectrum of familial hypercholesterolemia in south-eastern Poland. | Sharifi M | Metabolism: clinical and experimental | 2016 | PMID: 26892515 |
| Clinical features of familial hypercholesterolemia in Korea: Predictors of pathogenic mutations and coronary artery disease - A study supported by the Korean Society of Lipidology and Atherosclerosis. | Shin DG | Atherosclerosis | 2015 | PMID: 26343872 |
| Systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction. | Thormaehlen AS | PLoS genetics | 2015 | PMID: 25647241 |
| Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. | Do R | Nature | 2015 | PMID: 25487149 |
| Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol. | Lange LA | American journal of human genetics | 2014 | PMID: 24507775 |
| The use of next-generation sequencing in clinical diagnosis of familial hypercholesterolemia. | Vandrovcova J | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 23680767 |
| Analysis of the frequency and spectrum of mutations recognised to cause familial hypercholesterolaemia in routine clinical practice in a UK specialist hospital lipid clinic. | Futema M | Atherosclerosis | 2013 | PMID: 23669246 |
| Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. | Bertolini S | Atherosclerosis | 2013 | PMID: 23375686 |
| Identification of LDLR mutations in two Chinese pedigrees with familial hypercholesterolemia. | Yao RE | Journal of pediatric endocrinology & metabolism : JPEM | 2012 | PMID: 23155708 |
| The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations. | Tichý L | Atherosclerosis | 2012 | PMID: 22698793 |
| Cardiovascular risk in relation to functionality of sequence variants in the gene coding for the low-density lipoprotein receptor: a study among 29,365 individuals tested for 64 specific low-density lipoprotein-receptor sequence variants. | Huijgen R | European heart journal | 2012 | PMID: 22390909 |
| Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children. | van der Graaf A | Circulation | 2011 | PMID: 21382890 |
| An APEX-based genotyping microarray for the screening of 168 mutations associated with familial hypercholesterolemia. | Dušková L | Atherosclerosis | 2011 | PMID: 21310417 |
| Update of the Portuguese Familial Hypercholesterolaemia Study. | Medeiros AM | Atherosclerosis | 2010 | PMID: 20828696 |
| The type of LDLR gene mutation predicts cardiovascular risk in children with familial hypercholesterolemia. | Guardamagna O | The Journal of pediatrics | 2009 | PMID: 19446849 |
| Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform. | Alonso R | Clinical biochemistry | 2009 | PMID: 19318025 |
| A novel method for determining functional LDL receptor activity in familial hypercholesterolemia: application of the CD3/CD28 assay in lymphocytes. | Tada H | Clinica chimica acta; international journal of clinical chemistry | 2009 | PMID: 19013141 |
| Update of Japanese common LDLR gene mutations and their phenotypes: Mild type mutation L547V might predominate in the Japanese population. | Miyake Y | Atherosclerosis | 2009 | PMID: 18718593 |
| Novel and recurrent mutations of the LDL receptor gene in Korean patients with familial hypercholesterolemia. | Kim JH | Molecules and cells | 2004 | PMID: 15359125 |
| Application of molecular genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program. | Leren TP | Seminars in vascular medicine | 2004 | PMID: 15199436 |
| Molecular genetic analysis of familial hypercholesterolemia: spectrum and regional difference of LDL receptor gene mutations in Japanese population. | Yu W | Atherosclerosis | 2002 | PMID: 12417285 |
| The UMD-LDLR database: additions to the software and 490 new entries to the database. | Villéger L | Human mutation | 2002 | PMID: 12124988 |
| Spectrum of low density lipoprotein receptor mutations in Czech hypercholesterolemic patients. | Kuhrová V | Human mutation | 2002 | PMID: 11754108 |
| R3531C mutation in the apolipoprotein B gene is not sufficient to cause hypercholesterolemia. | Rabès JP | Arteriosclerosis, thrombosis, and vascular biology | 2000 | PMID: 11031227 |
| Analysis of LDL receptor gene mutations in Italian patients with homozygous familial hypercholesterolemia. | Bertolini S | Arteriosclerosis, thrombosis, and vascular biology | 1999 | PMID: 9974426 |
| Mutations in the low-density lipoprotein receptor gene in Chinese familial hypercholesterolemia patients. | Mak YT | Arteriosclerosis, thrombosis, and vascular biology | 1998 | PMID: 9763532 |
| Characterization of mutations in the low density lipoprotein (LDL)-receptor gene in patients with homozygous familial hypercholesterolemia, and frequency of these mutations in FH patients in the United Kingdom. | Webb JC | Journal of lipid research | 1996 | PMID: 9026534 |
| Common mutations in the low-density-lipoprotein-receptor gene causing familial hypercholesterolemia in the Japanese population. | Maruyama T | Arteriosclerosis, thrombosis, and vascular biology | 1995 | PMID: 7583548 |
| Detection of the Pro664-Leu mutation in the low-density lipoprotein receptor and its relation to lipoprotein(a) levels in patients with familial hypercholesterolemia of Dutch ancestry from The Netherlands and Canada. | Defesche JC | Clinical genetics | 1992 | PMID: 1493640 |
| Identification and properties of the proline664-leucine mutant LDL receptor in South Africans of Indian origin. | Rubinsztein DC | Journal of lipid research | 1992 | PMID: 1464748 |
| Identification of the 664 proline to leucine mutation in the low density lipoprotein receptor in four unrelated patients with familial hypercholesterolaemia in the UK. | King-Underwood L | Clinical genetics | 1991 | PMID: 1884514 |
| Relationship between apolipoprotein(a) phenotype, lipoprotein(a) concentration in plasma, and low density lipoprotein receptor function in a large kindred with familial hypercholesterolemia due to the pro664----leu mutation in the LDL receptor gene. | Soutar AK | The Journal of clinical investigation | 1991 | PMID: 1830890 |
| Defective processing and binding of low-density lipoprotein receptors in fibroblasts from a familial hypercholesterolaemic subject. | Knight BL | European journal of biochemistry | 1989 | PMID: 2920733 |
| 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. | Soutar AK | Proceedings of the National Academy of Sciences of the United States of America | 1989 | PMID: 2726768 |
| Regulation of synthesis and cell content of the low-density-lipoprotein receptor protein in cultured fibroblasts from normal and familial hypercholesterolaemic subjects. | Knight BL | European journal of biochemistry | 1987 | PMID: 3816797 |
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Text-mined citations for this variant ...
HelpRecord last updated Oct 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.