subjects mutated among 2600 FH index cases screened = 4, family members =7
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1868TCA[1] (p.Ile624del)
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.
(10)
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
10
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.1868TCA[1] (p.Ile624del)
Variation ID: 252097 Accession: VCV000252097.11
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: 19p13.2 19: 11120113-11120115 (GRCh38) [ NCBI UCSC ] 19: 11230789-11230791 (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 Jul 29, 2016 May 1, 2024 Aug 16, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.1868TCA[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Ile624del inframe deletion NM_000527.4:c.1871_1873del NM_001195798.2:c.1868TCA[1] NP_001182727.1:p.Ile624del inframe deletion NM_001195799.2:c.1745TCA[1] NP_001182728.1:p.Ile583del inframe deletion NM_001195800.2:c.1364TCA[1] NP_001182729.1:p.Ile456del inframe deletion NM_001195803.2:c.1487TCA[1] NP_001182732.1:p.Ile497del inframe deletion NC_000019.10:g.11120114TCA[1] NC_000019.9:g.11230790TCA[1] NG_009060.1:g.35734TCA[1] NG_009060.1:g.35737_35739del LRG_274:g.35734TCA[1] LRG_274t1:c.1871_1873del - Protein change
- I624del, I456del, I497del, I583del
- Other names
- -
- Canonical SPDI
- NC_000019.10:11120112:ATCATCA:ATCA
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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 (7) |
criteria provided, multiple submitters, no conflicts
|
Sep 24, 2021 | RCV000237415.15 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 16, 2023 | RCV001042592.14 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 30, 2022 | RCV002411102.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 25, 2023 | RCV003477856.1 |
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. |
|
|---|---|---|---|---|---|
|
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: SCV000295730.2
First in ClinVar: Jul 29, 2016 Last updated: May 03, 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
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
|
|
|
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: SCV000503428.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
subjects mutated among 2600 FH index cases screened = 4, family members =7
Number of individuals with the variant: 4
|
|
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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: SCV000583901.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016
Comment:
ACMG Guidelines: Pathogenic (i)
|
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 : Probable FH
Secondary finding: no
|
|
|
Likely 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: SCV000588619.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017 |
Observation 1: Observation 2:
Comment on evidence:
Assay description:Heterologous cells (CHO), FACS assays
Result:
5-10% LDL-LDLR binding; <5% LDL-LDLR uptake; <5% cell surface LDLR
|
|
|
Likely 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: SCV000607651.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
Observation 1: Observation 2:
Comment on evidence:
Heterologous cells (CHO), FACS assays
Result:
5-10% LDL-LDLR binding; <5% LDL-LDLR uptake; <5% cell surface LDLR
|
|
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Pathogenic
(Sep 24, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002783304.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
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Pathogenic
(May 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004219959.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
The LDLR c.1871_1873del (p.Ile624del) variant has been reported in the published literature in multiple individuals with familial hypercholesterolemia (PMIDs: 11668640 (2001), 15199436 (2004), 19318025 (2009), … (more)
The LDLR c.1871_1873del (p.Ile624del) variant has been reported in the published literature in multiple individuals with familial hypercholesterolemia (PMIDs: 11668640 (2001), 15199436 (2004), 19318025 (2009), 20145306 (2010), 23375686 (2013), 28932795 (2015), 25378237 (2015), 27824480 (2017), and 31491741 (2019)). In vitro functional studies indicated that this variant results in significantly reduced LDLR expression, LDL binding, and LDL uptake compared to wild type (PMID: 25378237 (2015)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. (less)
|
|
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Pathogenic
(Aug 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001206284.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant, c.1871_1873del, results in the deletion of 1 amino acid(s) of the LDLR protein (p.Ile624del), but otherwise preserves the integrity of the reading frame. … (more)
This variant, c.1871_1873del, results in the deletion of 1 amino acid(s) of the LDLR protein (p.Ile624del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with familial hypercholesterolemia (PMID: 11668640, 15199436, 20145306, 23375686, 25378237, 25461735, 27824480, 28932795). ClinVar contains an entry for this variant (Variation ID: 252097). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects LDLR function (PMID: 25378237). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 30, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002723510.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.1871_1873delTCA pathogenic mutation (also known as p.I624del) is located in coding exon 13 of the LDLR gene. This pathogenic mutation results from an in-frame … (more)
The c.1871_1873delTCA pathogenic mutation (also known as p.I624del) is located in coding exon 13 of the LDLR gene. This pathogenic mutation results from an in-frame TCA deletion at nucleotide positions 1871 to 1873. This results in the in-frame deletion of an isoleucine at codon 624. This variant (also known as p.I603del) has been detected in several unrelated individuals with familial hypercholesterolemia (FH), FH cohorts, and cohorts referred for FH genetic testing (Leren TP et al. Atherosclerosis, 2021 04;322:61-66; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909; Tada H et al. J Clin Lipidol 2020 Mar;14:346-351.e9; Gabová D et al. Physiol Res, 2017 03;66:75-84; Etxebarria A et al. Hum Mutat, 2015 Jan;36:129-41; Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Chmara M et al. J Appl Genet, 2010;51:95-106). In a functional study, this variant was shown to result in significantly reduced LDLR expression, LDL binding, and LDL uptake compared to wild type (Etxebarria A et al. Hum Mutat, 2015 Jan;36:129-41). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
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: SCV000606548.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
Comment:
Comment:
The LDLR c.1871_1873del (p.Ile624del) variant has been reported in the published literature in multiple individuals with familial hypercholesterolemia (PMIDs: 11668640 (2001), 15199436 (2004), 19318025 (2009), 20145306 (2010), 23375686 (2013), 28932795 (2015), 25378237 (2015), 27824480 (2017), and 31491741 (2019)). In vitro functional studies indicated that this variant results in significantly reduced LDLR expression, LDL binding, and LDL uptake compared to wild type (PMID: 25378237 (2015)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Comment:
This variant, c.1871_1873del, results in the deletion of 1 amino acid(s) of the LDLR protein (p.Ile624del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with familial hypercholesterolemia (PMID: 11668640, 15199436, 20145306, 23375686, 25378237, 25461735, 27824480, 28932795). ClinVar contains an entry for this variant (Variation ID: 252097). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects LDLR function (PMID: 25378237). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.1871_1873delTCA pathogenic mutation (also known as p.I624del) is located in coding exon 13 of the LDLR gene. This pathogenic mutation results from an in-frame TCA deletion at nucleotide positions 1871 to 1873. This results in the in-frame deletion of an isoleucine at codon 624. This variant (also known as p.I603del) has been detected in several unrelated individuals with familial hypercholesterolemia (FH), FH cohorts, and cohorts referred for FH genetic testing (Leren TP et al. Atherosclerosis, 2021 04;322:61-66; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909; Tada H et al. J Clin Lipidol 2020 Mar;14:346-351.e9; Gabová D et al. Physiol Res, 2017 03;66:75-84; Etxebarria A et al. Hum Mutat, 2015 Jan;36:129-41; Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Chmara M et al. J Appl Genet, 2010;51:95-106). In a functional study, this variant was shown to result in significantly reduced LDLR expression, LDL binding, and LDL uptake compared to wild type (Etxebarria A et al. Hum Mutat, 2015 Jan;36:129-41). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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. |
Comment:
subjects mutated among 2600 FH index cases screened = 4, family members =7
Comment:
The LDLR c.1871_1873del (p.Ile624del) variant has been reported in the published literature in multiple individuals with familial hypercholesterolemia (PMIDs: 11668640 (2001), 15199436 (2004), 19318025 (2009), 20145306 (2010), 23375686 (2013), 28932795 (2015), 25378237 (2015), 27824480 (2017), and 31491741 (2019)). In vitro functional studies indicated that this variant results in significantly reduced LDLR expression, LDL binding, and LDL uptake compared to wild type (PMID: 25378237 (2015)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Comment:
This variant, c.1871_1873del, results in the deletion of 1 amino acid(s) of the LDLR protein (p.Ile624del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with familial hypercholesterolemia (PMID: 11668640, 15199436, 20145306, 23375686, 25378237, 25461735, 27824480, 28932795). ClinVar contains an entry for this variant (Variation ID: 252097). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects LDLR function (PMID: 25378237). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.1871_1873delTCA pathogenic mutation (also known as p.I624del) is located in coding exon 13 of the LDLR gene. This pathogenic mutation results from an in-frame TCA deletion at nucleotide positions 1871 to 1873. This results in the in-frame deletion of an isoleucine at codon 624. This variant (also known as p.I603del) has been detected in several unrelated individuals with familial hypercholesterolemia (FH), FH cohorts, and cohorts referred for FH genetic testing (Leren TP et al. Atherosclerosis, 2021 04;322:61-66; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909; Tada H et al. J Clin Lipidol 2020 Mar;14:346-351.e9; Gabová D et al. Physiol Res, 2017 03;66:75-84; Etxebarria A et al. Hum Mutat, 2015 Jan;36:129-41; Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Chmara M et al. J Appl Genet, 2010;51:95-106). In a functional study, this variant was shown to result in significantly reduced LDLR expression, LDL binding, and LDL uptake compared to wild type (Etxebarria A et al. Hum Mutat, 2015 Jan;36:129-41). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Diagnosis of familial hypercholesterolemia in a large cohort of Italian genotyped hypercholesterolemic patients. | Noto D | Atherosclerosis | 2022 | PMID: 35339733 |
| Lipoprotein(a) in hereditary hypercholesterolemia: Influence of the genetic cause, defective gene and type of mutation. | Marco-Benedí V | Atherosclerosis | 2022 | PMID: 34456049 |
| 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 |
| A catalog of the pathogenic mutations of LDL receptor gene in Japanese familial hypercholesterolemia. | Tada H | Journal of clinical lipidology | 2020 | PMID: 32331935 |
| Impact of LDLR and PCSK9 pathogenic variants in Japanese heterozygous familial hypercholesterolemia patients. | Hori M | Atherosclerosis | 2019 | PMID: 31491741 |
| The molecular genetic background of familial hypercholesterolemia: data from the Slovak nation-wide survey. | Gabčová D | Physiological research | 2017 | PMID: 27824480 |
| Lipoprotein metabolism in familial hypercholesterolemia: Serial assessment using a one-step ultracentrifugation method. | Tada H | Practical laboratory medicine | 2015 | PMID: 28932795 |
| Familial hypercholesterolemia in Brazil: cascade screening program, clinical and genetic aspects. | Jannes CE | Atherosclerosis | 2015 | PMID: 25461735 |
| Functional characterization and classification of frequent low-density lipoprotein receptor variants. | Etxebarria A | Human mutation | 2015 | PMID: 25378237 |
| Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. | Bertolini S | Atherosclerosis | 2013 | PMID: 23375686 |
| Low-density lipoprotein receptor gene familial hypercholesterolemia variant database: update and pathological assessment. | Usifo E | Annals of human genetics | 2012 | PMID: 22881376 |
| Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations. | Chmara M | Journal of applied genetics | 2010 | PMID: 20145306 |
| Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform. | Alonso R | Clinical biochemistry | 2009 | PMID: 19318025 |
| 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 |
| Molecular genetics of familial hypercholesterolemia in Spain: Ten novel LDLR mutations and population analysis. | García-García AB | Human mutation | 2001 | PMID: 11668640 |
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Text-mined citations for this variant ...
HelpRecord last updated Nov 10, 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.