ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1576C>T (p.Pro526Ser)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000527.5(LDLR):c.1576C>T (p.Pro526Ser)
Variation ID: 183120 Accession: VCV000183120.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11113752 (GRCh38) [ NCBI UCSC ] 19: 11224428 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Feb 28, 2015 Aug 11, 2024 Jun 9, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.1576C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Pro526Ser missense NM_001195798.2:c.1576C>T NP_001182727.1:p.Pro526Ser missense NM_001195799.2:c.1453C>T NP_001182728.1:p.Pro485Ser missense NM_001195800.2:c.1072C>T NP_001182729.1:p.Pro358Ser missense NM_001195803.2:c.1195C>T NP_001182732.1:p.Pro399Ser missense NC_000019.10:g.11113752C>T NC_000019.9:g.11224428C>T NG_009060.1:g.29372C>T LRG_274:g.29372C>T LRG_274t1:c.1576C>T LRG_274p1:p.Pro526Ser P01130:p.Pro526Ser - Protein change
- P526S, P485S, P358S, P399S
- Other names
- FH Cincinnati-3
- NM_000527.5(LDLR):c.1576C>T
- Canonical SPDI
- NC_000019.10:11113751:C:T
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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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
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 | ||
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HI score
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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. |
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LDLR | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4059 | 4334 |
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. |
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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Mar 22, 2023 | RCV000161994.16 | |
Pathogenic (1) |
criteria provided, single submitter
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May 3, 2024 | RCV002399589.4 | |
Uncertain significance (7) |
reviewed by expert panel
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Jun 9, 2021 | RCV000238217.15 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 27, 2024 | RCV000775072.12 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 14, 2020 | RCV004017445.1 |
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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Uncertain significance
(Jun 09, 2021)
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reviewed by expert panel
Method: curation
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Hypercholesterolemia, familial, 1
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV001960928.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
Comment:
NM_000527.5(LDLR):c.1576C>T (p.Pro526Ser) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4 and PS4_Supportive) as defined by … (more)
NM_000527.5(LDLR):c.1576C>T (p.Pro526Ser) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4 and PS4_Supportive) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00002326 (0.002%) in European-non Finnish exomes (gnomAD v2.1.1). PP3 - REVEL: 0,952. PP4 - Variant meets PM2. Variant identified in 5 index cases (1 case from Color laboratory with Simon-Broome criteria; 1 case from GeneDx laboratory with Simon Broome criteria; 1 cases from University of British Columbia with DLCN criteria; 2 cases fulfilling Simeon-Broome criteria published in PMID: 9259195). PS4_supporting - Variant meets PM2. Variant identified in 5 index cases. (less)
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Likely pathogenic
(Mar 25, 2016)
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criteria provided, single submitter
Method: literature only
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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LDLR-LOVD, British Heart Foundation
Accession: SCV000295505.2
First in ClinVar: Jul 29, 2016 Last updated: Feb 08, 2018 |
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
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Likely pathogenic
(Mar 03, 2019)
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criteria provided, single submitter
Method: research
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Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
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Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia
Accession: SCV001432657.1
First in ClinVar: Sep 19, 2020 Last updated: Sep 19, 2020 |
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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Likely pathogenic
(Jun 29, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002501974.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Likely pathogenic
(Aug 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemia
Affected status: no
Allele origin:
germline
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National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health
Accession: SCV002522192.2
First in ClinVar: Jun 03, 2022 Last updated: Oct 07, 2023 |
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Pathogenic
(Jan 27, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000627019.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 526 of the LDLR protein (p.Pro526Ser). … (more)
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 526 of the LDLR protein (p.Pro526Ser). This variant is present in population databases (rs730882106, gnomAD 0.002%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 9259195, 11462246, 27497240; Invitae). This variant is also known as p.Pro505Ser. ClinVar contains an entry for this variant (Variation ID: 183120). 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: 1301956, 25647241). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Dec 16, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
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Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix
Accession: SCV000503367.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
subjects mutated among 2600 FH index cases screened = 4 , family members = 3 / FH-Cincinnati-3, 5% to 15% LDLR Activity / Software predictions: … (more)
subjects mutated among 2600 FH index cases screened = 4 , family members = 3 / FH-Cincinnati-3, 5% to 15% LDLR Activity / Software predictions: Damaging (less)
Number of individuals with the variant: 4
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Pathogenic
(Mar 30, 2017)
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criteria provided, single submitter
Method: clinical testing
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Familial Hypercholesterolemia
Affected status: yes
Allele origin:
germline
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U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille
Accession: SCV000583850.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016
Comment:
ACMG Guidelines: Pathogenic (ii)
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Number of individuals with the variant: 4
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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Uncertain significance
(Mar 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001792713.4
First in ClinVar: Aug 20, 2021 Last updated: Sep 07, 2023 |
Comment:
Reported in several individuals with FH, some of which harbored an additional FH-related variant (Hobbs et al., 1992; Day et al., 1997; Nauck et al., … (more)
Reported in several individuals with FH, some of which harbored an additional FH-related variant (Hobbs et al., 1992; Day et al., 1997; Nauck et al., 2001; Thormaehlen et al., 2015; Maurer et al., 2016); Also known as p.P505S and FH-Cincinnati-3; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25647241, 27497240, 1301956, 25487149, 9259195, 30586733, 31401775, 31447099, 11462246, 34037665, 31345425, 26582918, 35753512, 10357843, 10208479, 19837725) (less)
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Likely pathogenic
(Nov 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001134254.4
First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.000023 (3/128988 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more)
The frequency of this variant in the general population, 0.000023 (3/128988 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with hypercholesterolemia (PMID: 9259195 (1997), 11462246 (2001), 27497240 (2016), 31345425 (2019), 34037665 (2021)). Functional studies have reported that this variant is damaging by causing LDLR activity to decrease to 5% to 15% of wildtype (PMID: 1301956 (1992)) that is likely due to an error in biosynthesis or turnover (PMID: 25647241 (2015)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. (less)
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Likely pathogenic
(Oct 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000909174.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces proline with serine at codon 526 in the third LDLR type B repeat of the EGF precursor homology domain of the … (more)
This missense variant replaces proline with serine at codon 526 in the third LDLR type B repeat of the EGF precursor homology domain of the LDLR protein. This variant is also known as p.Pro505Ser in the mature protein; FH Cincinnati-3. 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). A functional study has shown that this variant interferes with protein transport and significantly affects LDLR biosynthesis or turnover (PMID: 25647241). Another functional study has shown significantly reduced LDLR activity (5-15% of the wild type) in cells from an individual with heterozygous hypercholesterolemia (PMID: 1301956). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 1301956, 9259195, 10208479, 11462246, 27497240, 31345425, 34037665; Color internal data). This variant has been identified in 3/282624 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Likely Pathogenic
(Jan 08, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004822480.1
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)
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Comment:
This missense variant replaces proline with serine at codon 526 in the third LDLR type B repeat of the EGF precursor homology domain of the … (more)
This missense variant replaces proline with serine at codon 526 in the third LDLR type B repeat of the EGF precursor homology domain of the LDLR protein. This variant is also known as p.Pro505Ser in the mature protein; FH Cincinnati-3. 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). A functional study has shown that this variant interferes with protein transport and significantly affects LDLR biosynthesis or turnover (PMID: 25647241). Another functional study has shown significantly reduced LDLR activity (5-15% of the wild type) in cells from an individual with heterozygous hypercholesterolemia (PMID: 1301956). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 1301956, 9259195, 10208479, 11462246, 27497240, 31345425, 34037665; Color internal data). This variant has been identified in 3/282624 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
Number of individuals with the variant: 7
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Likely Pathogenic
(Apr 14, 2020)
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criteria provided, single submitter
Method: clinical testing
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Homozygous familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000539511.2
First in ClinVar: Apr 09, 2017 Last updated: Apr 20, 2024 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
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Pathogenic
(May 03, 2024)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002710067.3
First in ClinVar: Nov 29, 2022 Last updated: Aug 11, 2024 |
Comment:
The p.P526S pathogenic mutation (also known as c.1576C>T and p.P505S), located in coding exon 10 of the LDLR gene, results from a C to T … (more)
The p.P526S pathogenic mutation (also known as c.1576C>T and p.P505S), located in coding exon 10 of the LDLR gene, results from a C to T substitution at nucleotide position 1576. The proline at codon 526 is replaced by serine, an amino acid with similar properties. This variant has been detected in individuals with familial hypercholesterolemia (FH); reduced LDL uptake was observed in assays performed on patient fibroblasts as well as in in vitro assays (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Day IN et al. Hum. Mutat., 1997;10:116-27; Nauck MS et al. Hum. Mutat., 2001 Aug;18:165-6; Maurer F et al. Swiss Med Wkly, 2016 Aug;146:w14326; Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855). Based on internal structural analysis, this variant is expected to be structurally disruptive (Rudenko G et al. Science. 2002 Dec;298(5602):2353-8; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Likely pathogenic
(May 29, 2017)
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no assertion criteria provided
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
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Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
Accession: SCV000680104.1
First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018 |
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not provided
(-)
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no classification provided
(in vitro)
Method: in vitro
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not provided
Affected status: not applicable
Allele origin:
not applicable
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Dept. of Genetics and Pharmacogenomics, Merck Research Labs
Accession: SCV000189569.1
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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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: SCV000189569.1
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Comment:
disruptive missense
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis. | Sturm AC | JAMA cardiology | 2021 | PMID: 34037665 |
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 |
Risk of Premature Atherosclerotic Disease in Patients With Monogenic Versus Polygenic Familial Hypercholesterolemia. | Trinder M | Journal of the American College of Cardiology | 2019 | PMID: 31345425 |
Whole-Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized With Early-Onset Myocardial Infarction. | Khera AV | Circulation | 2019 | PMID: 30586733 |
Identification and molecular characterisation of Lausanne Institutional Biobank participants with familial hypercholesterolaemia - a proof-of-concept study. | Maurer F | Swiss medical weekly | 2016 | PMID: 27497240 |
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 |
Structure of the LDL receptor extracellular domain at endosomal pH. | Rudenko G | Science (New York, N.Y.) | 2002 | PMID: 12459547 |
Identification of recurrent and novel mutations in the LDL receptor gene in German patients with familial hypercholesterolemia. | Nauck MS | Human mutation | 2001 | PMID: 11462246 |
The type of mutation in the low density lipoprotein receptor gene influences the cholesterol-lowering response of the HMG-CoA reductase inhibitor simvastatin in patients with heterozygous familial hypercholesterolaemia. | Heath KE | Atherosclerosis | 1999 | PMID: 10208479 |
Spectrum of LDL receptor gene mutations in heterozygous familial hypercholesterolemia. | Day IN | Human mutation | 1997 | PMID: 9259195 |
Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. | Hobbs HH | Human mutation | 1992 | PMID: 1301956 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/fd1d2de9-2acd-4e4a-820d-02e74d6b59b6 | - | - | - | - |
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Text-mined citations for rs730882106 ...
HelpRecord last updated Sep 08, 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.