NM_000527.5(LDLR):c.2096C>T (p.Pro699Leu) variant is classified as Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (BS4, PP1_Strong and PP3) 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: BS4 - Variant does not segregate with FH phenotype in 11 informative meioses in 6 families (Laboratory of Genetics and Molecular Cardiology). PP1_strong - Variant segregates with FH phenotype in 58 informative meioses in 9 families from Laboratory of Genetics and Molecular Cardiology. PP3 - REVEL: 0,92.
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.2096C>T (p.Pro699Leu)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Uncertain significance
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000527.5(LDLR):c.2096C>T (p.Pro699Leu)
Variation ID: 252219 Accession: VCV000252219.41
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11120478 (GRCh38) [ NCBI UCSC ] 19: 11231154 (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 Dec 17, 2016 Oct 13, 2024 Jun 18, 2021 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.2096C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Pro699Leu missense NM_001195798.2:c.2096C>T NP_001182727.1:p.Pro699Leu missense NM_001195799.2:c.1973C>T NP_001182728.1:p.Pro658Leu missense NM_001195800.2:c.1592C>T NP_001182729.1:p.Pro531Leu missense NM_001195803.2:c.1606+245C>T intron variant NC_000019.10:g.11120478C>T NC_000019.9:g.11231154C>T NG_009060.1:g.36098C>T LRG_274:g.36098C>T LRG_274t1:c.2096C>T LRG_274p1:p.Pro699Leu P01130:p.Pro699Leu - Protein change
- P699L, P531L, P658L
- Other names
-
NP_000518.1:p.P699L
NM_000527.5(LDLR):c.2096C>T
- Canonical SPDI
- NC_000019.10:11120477:C:T
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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. |
|---|---|---|---|---|
| Uncertain significance (13) |
reviewed by expert panel
|
Jun 18, 2021 | RCV000237906.22 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 24, 2024 | RCV000589820.14 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Mar 26, 2019 | RCV000826172.6 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
May 3, 2024 | RCV001284644.10 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Feb 27, 2024 | RCV002418071.3 |
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
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 18, 2021)
|
reviewed by expert panel
Method: curation
|
Hypercholesterolemia, familial, 1
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV001960938.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
Comment:
NM_000527.5(LDLR):c.2096C>T (p.Pro699Leu) variant is classified as Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (BS4, PP1_Strong and PP3) as defined by the ClinGen Familial … (more)
NM_000527.5(LDLR):c.2096C>T (p.Pro699Leu) variant is classified as Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (BS4, PP1_Strong and PP3) 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: BS4 - Variant does not segregate with FH phenotype in 11 informative meioses in 6 families (Laboratory of Genetics and Molecular Cardiology). PP1_strong - Variant segregates with FH phenotype in 58 informative meioses in 9 families from Laboratory of Genetics and Molecular Cardiology. PP3 - REVEL: 0,92. (less)
|
|
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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: SCV000295871.2
First in ClinVar: Jul 29, 2016 Last updated: May 26, 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
Observation 8:
Number of individuals with the variant: 1
|
|
|
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: SCV000484739.1
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: SCV000503463.1
First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016 |
Comment:
subject mutated among 2600 FH index cases screened = 1 , family members = 3 with co-segregation / previously described in association with FH/software prediction … (more)
subject mutated among 2600 FH index cases screened = 1 , family members = 3 with co-segregation / previously described in association with FH/software prediction damaging (less)
Number of individuals with the variant: 1
|
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Likely pathogenic
(Nov 05, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation
Additional submitter:
Centre of Molecular Biology and Gene Therapy, University Hospital Brno
Accession: SCV000540843.1
First in ClinVar: Apr 08, 2017 Last updated: Apr 08, 2017 |
Number of individuals with the variant: 1
Clinical Features:
Hypercholesterolemia (present)
Age: 40-49 years
Sex: male
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Tissue: Whole blood
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|
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Pathogenic
(Mar 30, 2017)
|
criteria provided, single submitter
Method: clinical testing
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Familial Hypercholesterolemia
Affected status: yes
Allele origin:
germline
|
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille
Accession: SCV000583929.1
First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017
Comment:
ACMG Guidelines: Pathogenic (ii)
|
Number of individuals with the variant: 1
Clinical Features:
Hyperbetalipoproteinemia (present) , Hypercholesterolemia (present)
Indication for testing: Familial Hypercholesterolemia
Geographic origin: France
Comment on evidence:
Dutch Lipid Clinic Scoring : Probable FH
Secondary finding: no
|
|
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Uncertain significance
(Mar 01, 2016)
|
criteria provided, single submitter
Method: research
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Study: HipercolBrasil
Accession: SCV000588634.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017 |
Comment on evidence:
%MAF(ExAC):0.001655
|
|
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Uncertain significance
(Mar 01, 2016)
|
criteria provided, single submitter
Method: research
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Fundacion Hipercolesterolemia Familiar
Study: SAFEHEART
Accession: SCV000607675.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
Comment on evidence:
%MAF(ExAC):0.001655
|
|
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Likely pathogenic
(Mar 26, 2019)
|
criteria provided, single submitter
Method: clinical testing
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Homozygous familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000967711.2
First in ClinVar: Aug 26, 2019 Last updated: Jul 06, 2020 |
Comment:
The p.Pro699Leu variant in LDLR (also reported as p.Pro678Leu in the literature) has been reported in the heterozygous state at least 11 individuals with familial … (more)
The p.Pro699Leu variant in LDLR (also reported as p.Pro678Leu in the literature) has been reported in the heterozygous state at least 11 individuals with familial hypercholesterolemia (FH) and 7 individuals with suspected FH (Thiart 2000, Fouchier 2001, Van Gaal 2001, Huijgen 2011, Tichy 2012, Bertolini 2013, Jannes 2015, Wang 2016, Sharif 2016). It was also identified in 1 individual with homozygous FH who had a second pathogenic loss of function variant in LDLR (Schuster 1995). This variant was also present in this individual's father who had normal cholesterol levels, suggesting reduced penetrance. The p.Pro699Leu variant has been reported by other clinical laboratories in ClinVar (Variation ID# 252219) and has been identified in 9/24032 African chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org; dbSNP rs201573863). This frequency is low enough to be consistent with the frequency of FH in the general population. Computational prediction tools and conservation analysis suggest that the p.Pro699Leu variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Pro699Leu variant is likely pathogenic. The ACMG/AMP Criteria applied (Richards 2015): PS4, PM2_supporting, PP3. (less)
Number of individuals with the variant: 3
|
|
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Pathogenic
(Sep 10, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
|
Division of Medical Genetics, University of Washington
Study: CSER_CHARM
Accession: SCV001424793.1 First in ClinVar: Aug 03, 2020 Last updated: Aug 03, 2020 |
Comment:
This variant has an overall allele frequency of 0.00004 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved … (more)
This variant has an overall allele frequency of 0.00004 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. This variant has been reported in the literature in multiple individuals and families with familial hypercholesterolemia (Schuster 1995, Thiart 2000, Fouchier 2001, Van Gaal 2001, Huijgen 2011, Tichy 2012, Bertolini 2013, Janness 2015, Sharifi 2016, Wang 2016). Thus, this variant is interpreted as pathogenic. (less)
Indication for testing: family history of breast cancer
Secondary finding: yes
|
|
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Pathogenic
(Nov 21, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001470534.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The best available variant frequency is uninformative because it is below the disease allele frequency. Predicted to have a damaging effect on the protein. In … (more)
The best available variant frequency is uninformative because it is below the disease allele frequency. Predicted to have a damaging effect on the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. (less)
|
|
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Likely pathogenic
(Oct 31, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001754790.1
First in ClinVar: Jul 24, 2021 Last updated: Jul 24, 2021 |
Comment:
The c.2096C>T (p.Pro699Leu) variant in exon 14 of LDLR gene results in an amino acid change at residue 699 from a proline to a leucine. … (more)
The c.2096C>T (p.Pro699Leu) variant in exon 14 of LDLR gene results in an amino acid change at residue 699 from a proline to a leucine. This variant has been reported in multiple unrelated individuals and families with familial hypercholesterolemia (PMID: 21642693, 7489239, 21310417, 26892515, 25461735, 10882754). Multiple lines of in silico algorithms have predicted this p.Pro699Leu change to be deleterious. Functional studies (PMID: 20089850) demonstrated that the mutant protein misfolded with a loss of normal protein tracking pattern. Therefore, this variant c.2096C>T (p.Pro699Leu) of LDLR is classified as likely pathogenic. (less)
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|
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Pathogenic
(Sep 21, 2023)
|
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: SCV000697211.2
First in ClinVar: Mar 17, 2018 Last updated: Nov 04, 2023 |
Comment:
Variant summary: LDLR c.2096C>T (p.Pro699Leu) 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.2096C>T (p.Pro699Leu) 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 2e-05 in 251028 control chromosomes. c.2096C>T has been reported in the literature as a heterozygous genotype in multiple individuals affected with autosomal dominant Familial Hypercholesterolemia (example, Schuster_1995, Huijgen_2012, Bertolini_2013, Jannes_2015, Wang_2016, Tichy_2012, Ahmad_2012, Marco-Benedi_2022, Sharifi_2016) to include at-least one compound heterozygous proband with severe Hypercholesterolemia whose obligate carrier father with this variant was reportedly unaffected, i.e., normal cholesterol levels at age 39 (Schuster_1995). This same study also reported co-segregation with Hypercholesterolemia in a second family but did not provide primary evidence supporting this finding (Schuster_1995). As the variant allele was transmitted much more often than the reference allele to affected members in tested families, these data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23064986, 23375686, 22698793, 22390909, 25461735, Wang_2016 has NO_PMID, 7489239, 34456049, 26892515). Multiple submitters including an expert panel (ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel) have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments but a predominant consensus as Pathogenic/Likely pathogenic (n=12) and VUS (n=4 to include the Expert Panel). Some submitters cite overlapping evidence utilized in the context of this evaluation while the Expert Panel cites both apparent non-segregation and co-segregation without providing primary evidence for independent corroboration. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Jan 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000544654.9
First in ClinVar: Apr 16, 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 699 of the LDLR protein (p.Pro699Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 699 of the LDLR protein (p.Pro699Leu). This variant is present in population databases (rs201573863, gnomAD 0.04%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 7489239, 10882754, 21310417, 21642693, 22390909, 23375686, 25461735, 26892515, 27765764). This variant is also known as Pro678Leu. ClinVar contains an entry for this variant (Variation ID: 252219). 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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|
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Likely pathogenic
(Nov 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000911498.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces proline with leucine at codon 699 in the EGF-like repeat C of the EGF precursor homology domain of the LDLR protein. … (more)
This missense variant replaces proline with leucine at codon 699 in the EGF-like repeat C of the EGF precursor homology domain of the LDLR protein. This variant is also known as p.Pro678Leu 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). A functional study using transfected HeLa cells has shown that this variant causes LDLR protein misfolding and retention in the endoplasmic reticulum (PMID: 20089850). This variant has been reported in over 20 individuals affected with familial hypercholesterolemia (PMID: 10882754, 11810272, 11851376, 19318025, 21310417, 21642693, 22698793, 23064986, 23375686, 26892515, 27824480, 33994402, 34037665, 35137788). While this variant has been shown to segregate with disease, with 58 informative meioses across 9 families, it has also shown non-segregation in 11 informative meioses across 6 families (ClinVar SCV001960938.1). This variant has been identified in 11/282422 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
(May 03, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002498865.5
First in ClinVar: Apr 16, 2022 Last updated: Sep 16, 2024 |
Comment:
Reported in the heterozygous state in numerous individuals from different ethnic backgrounds with a clinical diagnosis of FH (PMID: 10882754, 11810272, 11851376, 19318025, 21310417, 21642693, … (more)
Reported in the heterozygous state in numerous individuals from different ethnic backgrounds with a clinical diagnosis of FH (PMID: 10882754, 11810272, 11851376, 19318025, 21310417, 21642693, 22698793, 23375686, 24507775, 25461735, 26892515, 31106297, 35339733, 34456049, 35480308); Located in the third EGF-like repeat within the LDL-receptor EGF precursor homology domain (PMID: 12459547, 2988123); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(P678L); This variant is associated with the following publications: (PMID: 11810272, 21310417, 26892515, 10882754, 19318025, 23375686, 22390909, 11851376, 24507775, 21642693, 25461735, 22698793, 34040191, 32719484, 34037665, 33740630, 33303402, 30586733, 32041611, 35339733, 32220565, 23064986, 27824480, 34234266, 27765764, 33994402, 23769672, 31106297, 31447099, 37443404, 20506408, 29192238, 36769882, 12459547, 2988123, 20089850, 34363016, 34456049, 35480308, 28502495, 37409534, 7489239) (less)
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Likely pathogenic
(Apr 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004227683.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
BS4, PP1, PP3, PM3, PS4
Number of individuals with the variant: 1
|
|
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Uncertain significance
(May 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003816526.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Likely pathogenic
(Sep 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004562584.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The LDLR c.2096C>T p.Pro699Leu variant, also known as Pro678Leu, (rs201573863) is reported in the literature in several individuals and families with clinically diagnosed familial hypercholesterolemia … (more)
The LDLR c.2096C>T p.Pro699Leu variant, also known as Pro678Leu, (rs201573863) is reported in the literature in several individuals and families with clinically diagnosed familial hypercholesterolemia (selected publications: Ajufo 2021, Brown 2020, Lange 2014, Sun 2018), including a few homozygous or compound heterozygous individuals affected with severe disease (Santos 2014, Schuster 1995). This variant is also reported in ClinVar (Variation ID: 252219), and is found in the general population with an overall allele frequency of 0.0034% (11/282422 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.920). Based on available information, this variant is considered to be likely pathogenic. References: Ajufo E et al. A randomized controlled trial of genetic testing and cascade screening in familial hypercholesterolemia. Genet Med. 2021 Sep;23(9):1697-1704. PMID: 34040191. Brown EE et al. Incorporation of genetic testing significantly increases the number of individuals diagnosed with familial hypercholesterolemia. J Clin Lipidol. 2020 May-Jun;14(3):331-338. PMID: 32220565. Lange LA et al. Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol. Am J Hum Genet. 2014 Feb 6;94(2):233-45. PMID: 24507775. Santos RD. What are we able to achieve today for our patients with homozygous familial hypercholesterolaemia, and what are the unmet needs? Atheroscler Suppl. 2014 Sep;15(2):19-25. PMID: 25257073. Schuster H et al. Ten LDL receptor mutants explain one third of familial hypercholesterolemia in a German sample. Arterioscler Thromb Vasc Biol. 1995 Dec;15(12):2176-80. PMID: 7489239. Sun YV et al. Effects of Genetic Variants Associated with Familial Hypercholesterolemia on Low-Density Lipoprotein-Cholesterol Levels and Cardiovascular Outcomes in the Million Veteran Program. Circ Genom Precis Med. 2018 Dec;11(12):e002192. PMID: 31106297. (less)
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Likely pathogenic
(Feb 27, 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: SCV002726638.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.P699L variant (also known as c.2096C>T), located in coding exon 14 of the LDLR gene, results from a C to T substitution at nucleotide … (more)
The p.P699L variant (also known as c.2096C>T), located in coding exon 14 of the LDLR gene, results from a C to T substitution at nucleotide position 2096. The proline at codon 699 is replaced by leucine, an amino acid with similar properties. This variant, also known as p.P678L, has been reported in numerous familial hypercholesterolemia (FH) cohorts, though clinical details were limited in many of the studies (e.g., Thiart R et al. J. Med. Genet., 2000 Jul;37:514-9; Ahmad Z et al, Circ Cardiovasc Genet 2012 Dec; 5(6):666-75; Sharifi M et al. Metab. Clin. Exp., 2016 Mar;65:48-53; Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7; Wang J et al. Arterioscler. Thromb. Vasc. Biol., 2016 12;36:2439-2445; Gabová D et al. Physiol Res, 2017 Mar;66:75-84; Kawame H et al. J Hum Genet, 2021 Jul;). This alteration has also been described in the compound heterozygous or homozygous state in multiple probands with homozygous FH (Schuster H et al, Arterioscler. Thromb. Vasc. Biol. 1995 Dec; 15(12):2176-80; Santos RD. Atheroscler Suppl, 2014 Sep;15:19-25). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Likely pathogenic
(Sep 22, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV005373905.1
First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024 |
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Accession: SCV000606597.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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Comment:
Comment:
subject mutated among 2600 FH index cases screened = 1 , family members = 3 with co-segregation / previously described in association with FH/software prediction damaging
Comment:
The p.Pro699Leu variant in LDLR (also reported as p.Pro678Leu in the literature) has been reported in the heterozygous state at least 11 individuals with familial hypercholesterolemia (FH) and 7 individuals with suspected FH (Thiart 2000, Fouchier 2001, Van Gaal 2001, Huijgen 2011, Tichy 2012, Bertolini 2013, Jannes 2015, Wang 2016, Sharif 2016). It was also identified in 1 individual with homozygous FH who had a second pathogenic loss of function variant in LDLR (Schuster 1995). This variant was also present in this individual's father who had normal cholesterol levels, suggesting reduced penetrance. The p.Pro699Leu variant has been reported by other clinical laboratories in ClinVar (Variation ID# 252219) and has been identified in 9/24032 African chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org; dbSNP rs201573863). This frequency is low enough to be consistent with the frequency of FH in the general population. Computational prediction tools and conservation analysis suggest that the p.Pro699Leu variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Pro699Leu variant is likely pathogenic. The ACMG/AMP Criteria applied (Richards 2015): PS4, PM2_supporting, PP3.
Comment:
This variant has an overall allele frequency of 0.00004 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. This variant has been reported in the literature in multiple individuals and families with familial hypercholesterolemia (Schuster 1995, Thiart 2000, Fouchier 2001, Van Gaal 2001, Huijgen 2011, Tichy 2012, Bertolini 2013, Janness 2015, Sharifi 2016, Wang 2016). Thus, this variant is interpreted as pathogenic.
Comment:
The best available variant frequency is uninformative because it is below the disease allele frequency. Predicted to have a damaging effect on the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls.
Comment:
The c.2096C>T (p.Pro699Leu) variant in exon 14 of LDLR gene results in an amino acid change at residue 699 from a proline to a leucine. This variant has been reported in multiple unrelated individuals and families with familial hypercholesterolemia (PMID: 21642693, 7489239, 21310417, 26892515, 25461735, 10882754). Multiple lines of in silico algorithms have predicted this p.Pro699Leu change to be deleterious. Functional studies (PMID: 20089850) demonstrated that the mutant protein misfolded with a loss of normal protein tracking pattern. Therefore, this variant c.2096C>T (p.Pro699Leu) of LDLR is classified as likely pathogenic.
Comment:
Variant summary: LDLR c.2096C>T (p.Pro699Leu) 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 2e-05 in 251028 control chromosomes. c.2096C>T has been reported in the literature as a heterozygous genotype in multiple individuals affected with autosomal dominant Familial Hypercholesterolemia (example, Schuster_1995, Huijgen_2012, Bertolini_2013, Jannes_2015, Wang_2016, Tichy_2012, Ahmad_2012, Marco-Benedi_2022, Sharifi_2016) to include at-least one compound heterozygous proband with severe Hypercholesterolemia whose obligate carrier father with this variant was reportedly unaffected, i.e., normal cholesterol levels at age 39 (Schuster_1995). This same study also reported co-segregation with Hypercholesterolemia in a second family but did not provide primary evidence supporting this finding (Schuster_1995). As the variant allele was transmitted much more often than the reference allele to affected members in tested families, these data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23064986, 23375686, 22698793, 22390909, 25461735, Wang_2016 has NO_PMID, 7489239, 34456049, 26892515). Multiple submitters including an expert panel (ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel) have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments but a predominant consensus as Pathogenic/Likely pathogenic (n=12) and VUS (n=4 to include the Expert Panel). Some submitters cite overlapping evidence utilized in the context of this evaluation while the Expert Panel cites both apparent non-segregation and co-segregation without providing primary evidence for independent corroboration. Based on the evidence outlined above, the variant was 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 699 of the LDLR protein (p.Pro699Leu). This variant is present in population databases (rs201573863, gnomAD 0.04%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 7489239, 10882754, 21310417, 21642693, 22390909, 23375686, 25461735, 26892515, 27765764). This variant is also known as Pro678Leu. ClinVar contains an entry for this variant (Variation ID: 252219). 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.
Comment:
This missense variant replaces proline with leucine at codon 699 in the EGF-like repeat C of the EGF precursor homology domain of the LDLR protein. This variant is also known as p.Pro678Leu 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). A functional study using transfected HeLa cells has shown that this variant causes LDLR protein misfolding and retention in the endoplasmic reticulum (PMID: 20089850). This variant has been reported in over 20 individuals affected with familial hypercholesterolemia (PMID: 10882754, 11810272, 11851376, 19318025, 21310417, 21642693, 22698793, 23064986, 23375686, 26892515, 27824480, 33994402, 34037665, 35137788). While this variant has been shown to segregate with disease, with 58 informative meioses across 9 families, it has also shown non-segregation in 11 informative meioses across 6 families (ClinVar SCV001960938.1). This variant has been identified in 11/282422 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Comment:
Reported in the heterozygous state in numerous individuals from different ethnic backgrounds with a clinical diagnosis of FH (PMID: 10882754, 11810272, 11851376, 19318025, 21310417, 21642693, 22698793, 23375686, 24507775, 25461735, 26892515, 31106297, 35339733, 34456049, 35480308); Located in the third EGF-like repeat within the LDL-receptor EGF precursor homology domain (PMID: 12459547, 2988123); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(P678L); This variant is associated with the following publications: (PMID: 11810272, 21310417, 26892515, 10882754, 19318025, 23375686, 22390909, 11851376, 24507775, 21642693, 25461735, 22698793, 34040191, 32719484, 34037665, 33740630, 33303402, 30586733, 32041611, 35339733, 32220565, 23064986, 27824480, 34234266, 27765764, 33994402, 23769672, 31106297, 31447099, 37443404, 20506408, 29192238, 36769882, 12459547, 2988123, 20089850, 34363016, 34456049, 35480308, 28502495, 37409534, 7489239)
Comment:
BS4, PP1, PP3, PM3, PS4
Comment:
The LDLR c.2096C>T p.Pro699Leu variant, also known as Pro678Leu, (rs201573863) is reported in the literature in several individuals and families with clinically diagnosed familial hypercholesterolemia (selected publications: Ajufo 2021, Brown 2020, Lange 2014, Sun 2018), including a few homozygous or compound heterozygous individuals affected with severe disease (Santos 2014, Schuster 1995). This variant is also reported in ClinVar (Variation ID: 252219), and is found in the general population with an overall allele frequency of 0.0034% (11/282422 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.920). Based on available information, this variant is considered to be likely pathogenic. References: Ajufo E et al. A randomized controlled trial of genetic testing and cascade screening in familial hypercholesterolemia. Genet Med. 2021 Sep;23(9):1697-1704. PMID: 34040191. Brown EE et al. Incorporation of genetic testing significantly increases the number of individuals diagnosed with familial hypercholesterolemia. J Clin Lipidol. 2020 May-Jun;14(3):331-338. PMID: 32220565. Lange LA et al. Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol. Am J Hum Genet. 2014 Feb 6;94(2):233-45. PMID: 24507775. Santos RD. What are we able to achieve today for our patients with homozygous familial hypercholesterolaemia, and what are the unmet needs? Atheroscler Suppl. 2014 Sep;15(2):19-25. PMID: 25257073. Schuster H et al. Ten LDL receptor mutants explain one third of familial hypercholesterolemia in a German sample. Arterioscler Thromb Vasc Biol. 1995 Dec;15(12):2176-80. PMID: 7489239. Sun YV et al. Effects of Genetic Variants Associated with Familial Hypercholesterolemia on Low-Density Lipoprotein-Cholesterol Levels and Cardiovascular Outcomes in the Million Veteran Program. Circ Genom Precis Med. 2018 Dec;11(12):e002192. PMID: 31106297.
Comment:
The p.P699L variant (also known as c.2096C>T), located in coding exon 14 of the LDLR gene, results from a C to T substitution at nucleotide position 2096. The proline at codon 699 is replaced by leucine, an amino acid with similar properties. This variant, also known as p.P678L, has been reported in numerous familial hypercholesterolemia (FH) cohorts, though clinical details were limited in many of the studies (e.g., Thiart R et al. J. Med. Genet., 2000 Jul;37:514-9; Ahmad Z et al, Circ Cardiovasc Genet 2012 Dec; 5(6):666-75; Sharifi M et al. Metab. Clin. Exp., 2016 Mar;65:48-53; Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7; Wang J et al. Arterioscler. Thromb. Vasc. Biol., 2016 12;36:2439-2445; Gabová D et al. Physiol Res, 2017 Mar;66:75-84; Kawame H et al. J Hum Genet, 2021 Jul;). This alteration has also been described in the compound heterozygous or homozygous state in multiple probands with homozygous FH (Schuster H et al, Arterioscler. Thromb. Vasc. Biol. 1995 Dec; 15(12):2176-80; Santos RD. Atheroscler Suppl, 2014 Sep;15:19-25). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
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:
NM_000527.5(LDLR):c.2096C>T (p.Pro699Leu) variant is classified as Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (BS4, PP1_Strong and PP3) 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: BS4 - Variant does not segregate with FH phenotype in 11 informative meioses in 6 families (Laboratory of Genetics and Molecular Cardiology). PP1_strong - Variant segregates with FH phenotype in 58 informative meioses in 9 families from Laboratory of Genetics and Molecular Cardiology. PP3 - REVEL: 0,92.
Comment:
subject mutated among 2600 FH index cases screened = 1 , family members = 3 with co-segregation / previously described in association with FH/software prediction damaging
Comment:
The p.Pro699Leu variant in LDLR (also reported as p.Pro678Leu in the literature) has been reported in the heterozygous state at least 11 individuals with familial hypercholesterolemia (FH) and 7 individuals with suspected FH (Thiart 2000, Fouchier 2001, Van Gaal 2001, Huijgen 2011, Tichy 2012, Bertolini 2013, Jannes 2015, Wang 2016, Sharif 2016). It was also identified in 1 individual with homozygous FH who had a second pathogenic loss of function variant in LDLR (Schuster 1995). This variant was also present in this individual's father who had normal cholesterol levels, suggesting reduced penetrance. The p.Pro699Leu variant has been reported by other clinical laboratories in ClinVar (Variation ID# 252219) and has been identified in 9/24032 African chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org; dbSNP rs201573863). This frequency is low enough to be consistent with the frequency of FH in the general population. Computational prediction tools and conservation analysis suggest that the p.Pro699Leu variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Pro699Leu variant is likely pathogenic. The ACMG/AMP Criteria applied (Richards 2015): PS4, PM2_supporting, PP3.
Comment:
This variant has an overall allele frequency of 0.00004 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. This variant has been reported in the literature in multiple individuals and families with familial hypercholesterolemia (Schuster 1995, Thiart 2000, Fouchier 2001, Van Gaal 2001, Huijgen 2011, Tichy 2012, Bertolini 2013, Janness 2015, Sharifi 2016, Wang 2016). Thus, this variant is interpreted as pathogenic.
Comment:
The best available variant frequency is uninformative because it is below the disease allele frequency. Predicted to have a damaging effect on the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls.
Comment:
The c.2096C>T (p.Pro699Leu) variant in exon 14 of LDLR gene results in an amino acid change at residue 699 from a proline to a leucine. This variant has been reported in multiple unrelated individuals and families with familial hypercholesterolemia (PMID: 21642693, 7489239, 21310417, 26892515, 25461735, 10882754). Multiple lines of in silico algorithms have predicted this p.Pro699Leu change to be deleterious. Functional studies (PMID: 20089850) demonstrated that the mutant protein misfolded with a loss of normal protein tracking pattern. Therefore, this variant c.2096C>T (p.Pro699Leu) of LDLR is classified as likely pathogenic.
Comment:
Variant summary: LDLR c.2096C>T (p.Pro699Leu) 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 2e-05 in 251028 control chromosomes. c.2096C>T has been reported in the literature as a heterozygous genotype in multiple individuals affected with autosomal dominant Familial Hypercholesterolemia (example, Schuster_1995, Huijgen_2012, Bertolini_2013, Jannes_2015, Wang_2016, Tichy_2012, Ahmad_2012, Marco-Benedi_2022, Sharifi_2016) to include at-least one compound heterozygous proband with severe Hypercholesterolemia whose obligate carrier father with this variant was reportedly unaffected, i.e., normal cholesterol levels at age 39 (Schuster_1995). This same study also reported co-segregation with Hypercholesterolemia in a second family but did not provide primary evidence supporting this finding (Schuster_1995). As the variant allele was transmitted much more often than the reference allele to affected members in tested families, these data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23064986, 23375686, 22698793, 22390909, 25461735, Wang_2016 has NO_PMID, 7489239, 34456049, 26892515). Multiple submitters including an expert panel (ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel) have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments but a predominant consensus as Pathogenic/Likely pathogenic (n=12) and VUS (n=4 to include the Expert Panel). Some submitters cite overlapping evidence utilized in the context of this evaluation while the Expert Panel cites both apparent non-segregation and co-segregation without providing primary evidence for independent corroboration. Based on the evidence outlined above, the variant was 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 699 of the LDLR protein (p.Pro699Leu). This variant is present in population databases (rs201573863, gnomAD 0.04%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 7489239, 10882754, 21310417, 21642693, 22390909, 23375686, 25461735, 26892515, 27765764). This variant is also known as Pro678Leu. ClinVar contains an entry for this variant (Variation ID: 252219). 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.
Comment:
This missense variant replaces proline with leucine at codon 699 in the EGF-like repeat C of the EGF precursor homology domain of the LDLR protein. This variant is also known as p.Pro678Leu 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). A functional study using transfected HeLa cells has shown that this variant causes LDLR protein misfolding and retention in the endoplasmic reticulum (PMID: 20089850). This variant has been reported in over 20 individuals affected with familial hypercholesterolemia (PMID: 10882754, 11810272, 11851376, 19318025, 21310417, 21642693, 22698793, 23064986, 23375686, 26892515, 27824480, 33994402, 34037665, 35137788). While this variant has been shown to segregate with disease, with 58 informative meioses across 9 families, it has also shown non-segregation in 11 informative meioses across 6 families (ClinVar SCV001960938.1). This variant has been identified in 11/282422 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Comment:
Reported in the heterozygous state in numerous individuals from different ethnic backgrounds with a clinical diagnosis of FH (PMID: 10882754, 11810272, 11851376, 19318025, 21310417, 21642693, 22698793, 23375686, 24507775, 25461735, 26892515, 31106297, 35339733, 34456049, 35480308); Located in the third EGF-like repeat within the LDL-receptor EGF precursor homology domain (PMID: 12459547, 2988123); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(P678L); This variant is associated with the following publications: (PMID: 11810272, 21310417, 26892515, 10882754, 19318025, 23375686, 22390909, 11851376, 24507775, 21642693, 25461735, 22698793, 34040191, 32719484, 34037665, 33740630, 33303402, 30586733, 32041611, 35339733, 32220565, 23064986, 27824480, 34234266, 27765764, 33994402, 23769672, 31106297, 31447099, 37443404, 20506408, 29192238, 36769882, 12459547, 2988123, 20089850, 34363016, 34456049, 35480308, 28502495, 37409534, 7489239)
Comment:
BS4, PP1, PP3, PM3, PS4
Comment:
The LDLR c.2096C>T p.Pro699Leu variant, also known as Pro678Leu, (rs201573863) is reported in the literature in several individuals and families with clinically diagnosed familial hypercholesterolemia (selected publications: Ajufo 2021, Brown 2020, Lange 2014, Sun 2018), including a few homozygous or compound heterozygous individuals affected with severe disease (Santos 2014, Schuster 1995). This variant is also reported in ClinVar (Variation ID: 252219), and is found in the general population with an overall allele frequency of 0.0034% (11/282422 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.920). Based on available information, this variant is considered to be likely pathogenic. References: Ajufo E et al. A randomized controlled trial of genetic testing and cascade screening in familial hypercholesterolemia. Genet Med. 2021 Sep;23(9):1697-1704. PMID: 34040191. Brown EE et al. Incorporation of genetic testing significantly increases the number of individuals diagnosed with familial hypercholesterolemia. J Clin Lipidol. 2020 May-Jun;14(3):331-338. PMID: 32220565. Lange LA et al. Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol. Am J Hum Genet. 2014 Feb 6;94(2):233-45. PMID: 24507775. Santos RD. What are we able to achieve today for our patients with homozygous familial hypercholesterolaemia, and what are the unmet needs? Atheroscler Suppl. 2014 Sep;15(2):19-25. PMID: 25257073. Schuster H et al. Ten LDL receptor mutants explain one third of familial hypercholesterolemia in a German sample. Arterioscler Thromb Vasc Biol. 1995 Dec;15(12):2176-80. PMID: 7489239. Sun YV et al. Effects of Genetic Variants Associated with Familial Hypercholesterolemia on Low-Density Lipoprotein-Cholesterol Levels and Cardiovascular Outcomes in the Million Veteran Program. Circ Genom Precis Med. 2018 Dec;11(12):e002192. PMID: 31106297.
Comment:
The p.P699L variant (also known as c.2096C>T), located in coding exon 14 of the LDLR gene, results from a C to T substitution at nucleotide position 2096. The proline at codon 699 is replaced by leucine, an amino acid with similar properties. This variant, also known as p.P678L, has been reported in numerous familial hypercholesterolemia (FH) cohorts, though clinical details were limited in many of the studies (e.g., Thiart R et al. J. Med. Genet., 2000 Jul;37:514-9; Ahmad Z et al, Circ Cardiovasc Genet 2012 Dec; 5(6):666-75; Sharifi M et al. Metab. Clin. Exp., 2016 Mar;65:48-53; Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7; Wang J et al. Arterioscler. Thromb. Vasc. Biol., 2016 12;36:2439-2445; Gabová D et al. Physiol Res, 2017 Mar;66:75-84; Kawame H et al. J Hum Genet, 2021 Jul;). This alteration has also been described in the compound heterozygous or homozygous state in multiple probands with homozygous FH (Schuster H et al, Arterioscler. Thromb. Vasc. Biol. 1995 Dec; 15(12):2176-80; Santos RD. Atheroscler Suppl, 2014 Sep;15:19-25). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Effects of Different Types of Pathogenic Variants on Phenotypes of Familial Hypercholesterolemia. | Tada H | Frontiers in genetics | 2022 | PMID: 35480308 |
| Diagnosis of familial hypercholesterolemia in a large cohort of Italian genotyped hypercholesterolemic patients. | Noto D | Atherosclerosis | 2022 | PMID: 35339733 |
| Screening for Familial Hypercholesterolemia in Small Towns: Experience from 11 Brazilian Towns in the Hipercolbrasil Program. | Jannes CE | Arquivos brasileiros de cardiologia | 2022 | PMID: 35137788 |
| Lipoprotein(a) in hereditary hypercholesterolemia: Influence of the genetic cause, defective gene and type of mutation. | Marco-Benedí V | Atherosclerosis | 2022 | PMID: 34456049 |
| The return of individual genomic results to research participants: design and pilot study of Tohoku Medical Megabank Project. | Kawame H | Journal of human genetics | 2022 | PMID: 34234266 |
| Genetic Analysis in a Taiwanese Cohort of 750 Index Patients with Clinically Diagnosed Familial Hypercholesterolemia. | Huang CC | Journal of atherosclerosis and thrombosis | 2022 | PMID: 33994402 |
| Genetic testing in ambulatory cardiology clinics reveals high rate of findings with clinical management implications. | Murdock DR | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 34363016 |
| 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 |
| Combined hyperlipidemia is genetically similar to isolated hypertriglyceridemia. | Gill PK | Journal of clinical lipidology | 2021 | PMID: 33303402 |
| Population genetic screening efficiently identifies carriers of autosomal dominant diseases. | Grzymski JJ | Nature medicine | 2020 | PMID: 32719484 |
| 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 |
| 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 |
| Whole-Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized With Early-Onset Myocardial Infarction. | Khera AV | Circulation | 2019 | PMID: 30586733 |
| Effects of Genetic Variants Associated with Familial Hypercholesterolemia on Low-Density Lipoprotein-Cholesterol Levels and Cardiovascular Outcomes in the Million Veteran Program. | Sun YV | Circulation. Genomic and precision medicine | 2018 | PMID: 31106297 |
| Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals. | Yamaguchi-Kabata Y | Journal of human genetics | 2018 | PMID: 29192238 |
| Detection of common sequence variations of familial hypercholesterolemia in Taiwan using DNA mass spectrometry. | Chiou KR | Journal of clinical lipidology | 2017 | PMID: 28502495 |
| The molecular genetic background of familial hypercholesterolemia: data from the Slovak nation-wide survey. | Gabčová D | Physiological research | 2017 | PMID: 27824480 |
| Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically. | Wang J | Arteriosclerosis, thrombosis, and vascular biology | 2016 | PMID: 27765764 |
| The genetic spectrum of familial hypercholesterolemia in south-eastern Poland. | Sharifi M | Metabolism: clinical and experimental | 2016 | PMID: 26892515 |
| Familial hypercholesterolemia in Brazil: cascade screening program, clinical and genetic aspects. | Jannes CE | Atherosclerosis | 2015 | PMID: 25461735 |
| What are we able to achieve today for our patients with homozygous familial hypercholesterolaemia, and what are the unmet needs? | Santos RD | Atherosclerosis. Supplements | 2014 | PMID: 25257073 |
| Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol. | Lange LA | American journal of human genetics | 2014 | PMID: 24507775 |
| ERdj5 is the ER reductase that catalyzes the removal of non-native disulfides and correct folding of the LDL receptor. | Oka OB | Molecular cell | 2013 | PMID: 23769672 |
| Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. | Bertolini S | Atherosclerosis | 2013 | PMID: 23375686 |
| Low prevalence of mutations in known loci for autosomal dominant hypercholesterolemia in a multiethnic patient cohort. | Ahmad Z | Circulation. Cardiovascular genetics | 2012 | PMID: 23064986 |
| 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 |
| Assessment of carotid atherosclerosis in normocholesterolemic individuals with proven mutations in the low-density lipoprotein receptor or apolipoprotein B genes. | Huijgen R | Circulation. Cardiovascular genetics | 2011 | PMID: 21642693 |
| An APEX-based genotyping microarray for the screening of 168 mutations associated with familial hypercholesterolemia. | Dušková L | Atherosclerosis | 2011 | PMID: 21310417 |
| Functionality of sequence variants in the genes coding for the low-density lipoprotein receptor and apolipoprotein B in individuals with inherited hypercholesterolemia. | Huijgen R | Human mutation | 2010 | PMID: 20506408 |
| Calcium as a crucial cofactor for low density lipoprotein receptor folding in the endoplasmic reticulum. | Pena F | The Journal of biological chemistry | 2010 | PMID: 20089850 |
| Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform. | Alonso R | Clinical biochemistry | 2009 | PMID: 19318025 |
| Low-density lipoprotein receptor gene mutation analysis and clinical correlation in Belgian hypercholesterolaemics. | Van Gaal LF | Molecular and cellular probes | 2001 | PMID: 11851376 |
| The molecular basis of familial hypercholesterolemia in The Netherlands. | Fouchier SW | Human genetics | 2001 | PMID: 11810272 |
| Predominance of a 6 bp deletion in exon 2 of the LDL receptor gene in Africans with familial hypercholesterolaemia. | Thiart R | Journal of medical genetics | 2000 | PMID: 10882754 |
| Ten LDL receptor mutants explain one third of familial hypercholesterolemia in a German sample. | Schuster H | Arteriosclerosis, thrombosis, and vascular biology | 1995 | PMID: 7489239 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ea33bc95-d102-418a-b019-83d258dcad77 | - | - | - | - |
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Text-mined citations for this variant ...
HelpRecord last updated Oct 13, 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.