ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1955T>C (p.Met652Thr)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000527.5(LDLR):c.1955T>C (p.Met652Thr)
Variation ID: 226382 Accession: VCV000226382.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11120201 (GRCh38) [ NCBI UCSC ] 19: 11230877 (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 May 22, 2016 Aug 11, 2024 Aug 29, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.1955T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Met652Thr missense NM_001195798.2:c.1955T>C NP_001182727.1:p.Met652Thr missense NM_001195799.2:c.1832T>C NP_001182728.1:p.Met611Thr missense NM_001195800.2:c.1451T>C NP_001182729.1:p.Met484Thr missense NM_001195803.2:c.1574T>C NP_001182732.1:p.Met525Thr missense NC_000019.10:g.11120201T>C NC_000019.9:g.11230877T>C NG_009060.1:g.35821T>C LRG_274:g.35821T>C LRG_274t1:c.1955T>C LRG_274p1:p.Met652Thr - Protein change
- M652T, M484T, M611T, M525T
- Other names
- NM_000527.5(LDLR):c.1955T>C
- Canonical SPDI
- NC_000019.10:11120200:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
4064 | 4339 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Likely pathogenic (5) |
reviewed by expert panel
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Aug 29, 2022 | RCV000211590.13 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 28, 2024 | RCV000775082.15 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 19, 2024 | RCV002415887.3 |
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
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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
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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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Likely pathogenic
(Aug 29, 2022)
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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: SCV002817176.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
The NM_000527.5(LDLR):c.1955T>C (p.Met652Thr) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP4, PP1_Moderate and PS4_Supporting as defined by the … (more)
The NM_000527.5(LDLR):c.1955T>C (p.Met652Thr) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP4, PP1_Moderate and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follow: PM2_ Met : Allele frequency is 0.00005 (18394 alleles) in the East Asian subpopulation in GnomAD (gnomAD v2.1.1). PP4_Met : 2 patients with definite FH (1 from the Cardiovascular Genetics Laboratory - PathWest Laboratory Medicine WA - as defined by DLCN>6 and 1 from PMID: 20236128 as defined by Simon Broome score = definite). PS4_Supporting: 2 patients with definite FH (1 from the Cardiovascular Genetics Laboratory - PathWest Laboratory Medicine WA -with DLCN>6 and 1 from PMID: 20236128 with Simon Broome score = definite) and 1 case with untreated LDL-C=348 (Ambry Genetics). PMID:20829525 1 carrier was identified but the FH phenotype was evaluated only considering total and LDL-cholesterol levels above the 95 th percentile when compared with a sex- and age-matched French population. I will not consider this patient. PMID:22883975 1 carrier with clinical FH defined by DLCN score was reported. However, it is impossible to understand if the patient carrying the variant has a DLCN>6. I will not consider this patient. PMID: 28964736 1 carrier with clinical FH was reported in the cohort of ALTERNATIVE study which did not have a recorded diagnosis of FH, as they had very high baseline LDL-C levels (>5.0 mmol/L, ∼193 mg/dL).No data on FH its FC classification is reported. I will not consider this patient. PP1_Strong : Variant segregates with phenotype in 5 relatives in 1 family. (8 informative meiosis) (less)
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Uncertain significance
(Mar 25, 2016)
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criteria provided, single submitter
Method: literature only
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Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
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LDLR-LOVD, British Heart Foundation
Accession: SCV000295774.2
First in ClinVar: Jul 29, 2016 Last updated: Oct 10, 2018 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
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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: SCV000503437.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
subjects mutated among 2600 FH index cases screened = 2 / Other mutation at same codon/Software predictions: Conflicting
Number of individuals with the variant: 2
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Likely 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: SCV000583911.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016
Comment:
ACMG Guidelines: Likely Pathogenic (v)
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Number of individuals with the variant: 2
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 26, 2020)
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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: SCV000909186.3
First in ClinVar: May 20, 2019 Last updated: Jan 12, 2022 |
Comment:
This missense variant (also known as p.Met631Thr in the mature protein) replaces methionine with threonine at codon 652 of the LDLR protein. Computational prediction is … (more)
This missense variant (also known as p.Met631Thr in the mature protein) replaces methionine with threonine at codon 652 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 20236128, 20809525, 22883975, 28964736). It has been shown that this variant segregates with disease in one family (Al-Olabi et al 2019). This variant has been identified in 1/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Pathogenic
(Jan 28, 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: SCV000627024.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 652 of the LDLR protein (p.Met652Thr). … (more)
This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 652 of the LDLR protein (p.Met652Thr). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 20809525, 28964736; Invitae). ClinVar contains an entry for this variant (Variation ID: 226382). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(-)
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criteria provided, single submitter
Method: research
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Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
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Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine
Accession: SCV001482447.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
Age: 60-69 years
Sex: female
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Likely pathogenic
(Mar 19, 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: SCV002718365.3
First in ClinVar: Nov 29, 2022 Last updated: Aug 11, 2024 |
Comment:
The p.M652T variant (also known as c.1955T>C), located in coding exon 13 of the LDLR gene, results from a T to C substitution at nucleotide … (more)
The p.M652T variant (also known as c.1955T>C), located in coding exon 13 of the LDLR gene, results from a T to C substitution at nucleotide position 1955. The methionine at codon 652 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in individuals with familial hypercholesterolemia (FH) (Marduel M et al. Hum Mutat, 2010 Nov;31:E1811-24; Taylor A et al. Clin Genet, 2010 Jun;77:572-80; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4; Defesche JC et al. J Clin Lipidol, 2017 Sep;11:1338-1346.e7; Ajufo E et al. Genet Med, 2021 Sep;23:1697-1704). (Meshkov A et al. Genes (Basel), 2021 Jan;12; Ambry internal data). Internal structural analysis indicates this variant to be structurally disruptive (Rudenko G et al. Science. 2002 Dec;298(5602):2353-8). Additionally, an in vitro assay showed this alteration had a reduction of LDL uptake (Larrea-Sebal A et al. JACC Basic Transl Sci, 2021 Nov;6:815-827). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Jun 25, 2008)
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no assertion criteria provided
Method: clinical testing
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Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
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Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital
Accession: SCV000268651.1
First in ClinVar: May 22, 2016 Last updated: May 22, 2016 |
Number of individuals with the variant: 1
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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MLb-LDLr: A Machine Learning Model for Predicting the Pathogenicity of LDLr Missense Variants. | Larrea-Sebal A | JACC. Basic to translational science | 2021 | PMID: 34869944 |
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 |
The LDLR, APOB, and PCSK9 Variants of Index Patients with Familial Hypercholesterolemia in Russia. | Meshkov A | Genes | 2021 | PMID: 33418990 |
Analysis of publicly available LDLR, APOB, and PCSK9 variants associated with familial hypercholesterolemia: application of ACMG guidelines and implications for familial hypercholesterolemia diagnosis. | Chora JR | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29261184 |
Efficacy of alirocumab in 1191 patients with a wide spectrum of mutations in genes causative for familial hypercholesterolemia. | Defesche JC | Journal of clinical lipidology | 2017 | PMID: 28964736 |
Genetic analysis of familial hypercholesterolaemia in Western Australia. | Hooper AJ | Atherosclerosis | 2012 | PMID: 22883975 |
Molecular spectrum of autosomal dominant hypercholesterolemia in France. | Marduel M | Human mutation | 2010 | PMID: 20809525 |
Mutation detection rate and spectrum in familial hypercholesterolaemia patients in the UK pilot cascade project. | Taylor A | Clinical genetics | 2010 | PMID: 20236128 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7dfb2299-5dd6-4bd2-800b-7353722033a5 | - | - | - | - |
Text-mined citations for rs875989936 ...
HelpRecord last updated Sep 01, 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.