ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1503G>A (p.Ala501=)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000527.5(LDLR):c.1503G>A (p.Ala501=)
Variation ID: 251876 Accession: VCV000251876.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11113679 (GRCh38) [ NCBI UCSC ] 19: 11224355 (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 Jul 29, 2016 Sep 16, 2024 Aug 27, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.1503G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Ala501= synonymous NM_001195798.2:c.1503G>A NP_001182727.1:p.Ala501= synonymous NM_001195799.2:c.1380G>A NP_001182728.1:p.Ala460= synonymous NM_001195800.2:c.999G>A NP_001182729.1:p.Ala333= synonymous NM_001195803.2:c.1122G>A NP_001182732.1:p.Ala374= synonymous NC_000019.10:g.11113679G>A NC_000019.9:g.11224355G>A NG_009060.1:g.29299G>A LRG_274:g.29299G>A LRG_274t1:c.1503G>A - Protein change
- Other names
- NM_000527.5(LDLR):c.1503G>A
- Canonical SPDI
- NC_000019.10:11113678:G:A
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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.
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00003
The Genome Aggregation Database (gnomAD) 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00015
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
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 |
4073 | 4349 |
Conditions - Germline
Condition
Help
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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Uncertain significance (5) |
reviewed by expert panel
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Aug 27, 2022 | RCV000237830.10 | |
Uncertain significance (2) |
criteria provided, single submitter
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Jul 1, 2024 | RCV001193180.6 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Apr 27, 2023 | RCV001188900.9 | |
Uncertain significance (2) |
criteria provided, single submitter
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Dec 18, 2023 | RCV001727654.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 19, 2023 | RCV003298316.2 |
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
(Aug 27, 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: SCV002817174.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
The NM_000527.5(LDLR):c.1503G>A (p.Ala501=) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3) as defined by the … (more)
The NM_000527.5(LDLR):c.1503G>A (p.Ala501=) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3) 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 follows: PM2: PopMax MAF = 0.0002403 (0.02403%) in African/African American population exomes/genomes (gnomAD version). PP3: No REVEL score, splicing evaluation required. Functional data on splicing not available. B). Variant is exonic and at least 50bp upstream from canonical donor site and creates AG MES scores: de novo variant = 9.20; canonical acceptor = 6.76. Ratio de novo variant/canonical acceptor = 9.20/6.76 = 1.36 --- it is above 0.9 PP4: variant meets PM2, identified in 1 FH index case from PMID: 20145306 with WHO criteria, after alternative causes of high cholesterol were excluded. (less)
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Likely benign
(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: SCV000295473.2
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Number of individuals with the variant: 1
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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: SCV000583840.1
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: 3
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
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Uncertain significance
(Jan 22, 2020)
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criteria provided, single submitter
Method: curation
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Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001423092.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 04, 2022 |
Comment:
The c.1503G>A variant in LDLR has been reported in 4 individuals, including one Polish individual, with Familial Hypercholesterolemia (PMID: 20145306, Variation ID: 251876), and has … (more)
The c.1503G>A variant in LDLR has been reported in 4 individuals, including one Polish individual, with Familial Hypercholesterolemia (PMID: 20145306, Variation ID: 251876), and has been identified in 0.02403% (6/24970) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs368889457). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely benign and likely pathogenic in ClinVar (Variation ID: 251876). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Multiple missense variants in the same region as c.1503G>A have been reported in association with disease in ClinVar, suggesting that this variant is in a mutational hot spot and slightly supports pathogenicity (Variation ID: 251867, 251868, 251870, 265903, 251874, 251873, 251877). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3, PS4_Supporting, PM1_Supporting (Richards 2015). (less)
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Uncertain significance
(Oct 07, 2022)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001417719.2
First in ClinVar: Jul 16, 2020 Last updated: Feb 07, 2023 |
Comment:
This sequence change affects codon 501 of the LDLR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more)
This sequence change affects codon 501 of the LDLR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LDLR protein. This variant is present in population databases (rs368889457, gnomAD 0.03%). This variant has been observed in individual(s) with definite or suspected hypercholesterolemia (PMID: 20145306, 22881376). ClinVar contains an entry for this variant (Variation ID: 251876). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Apr 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001356075.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This synonymous variant causes a nucleotide substitution but does not change the encoded amino acid at codon 501 of the LDLR protein. Splice site prediction … (more)
This synonymous variant causes a nucleotide substitution but does not change the encoded amino acid at codon 501 of the LDLR protein. Splice site prediction tools suggest that this variant may impact RNA splicing through creation of a novel acceptor site. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 20145306, 30293936). This variant has been identified in 11/282836 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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Uncertain Significance
(Nov 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004822466.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This synonymous variant causes a nucleotide substitution but does not change the encoded amino acid at codon 501 of the LDLR protein. Splice site prediction … (more)
This synonymous variant causes a nucleotide substitution but does not change the encoded amino acid at codon 501 of the LDLR protein. Splice site prediction tools suggest that this variant may impact RNA splicing through creation of a novel acceptor site. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 20145306, 30293936). This variant has been identified in 11/282836 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)
Number of individuals with the variant: 11
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Uncertain significance
(Mar 19, 2023)
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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: SCV004000122.2
First in ClinVar: Jul 08, 2023 Last updated: May 01, 2024 |
Comment:
The c.1503G>A variant (also known as p.A501A), located in coding exon 10 of the LDLR gene, results from a G to A substitution at nucleotide … (more)
The c.1503G>A variant (also known as p.A501A), located in coding exon 10 of the LDLR gene, results from a G to A substitution at nucleotide position 1503. This nucleotide substitution does not change the alanine at codon 501. This alteration has been reported in familial hypercholesterolemia (FH) cohorts; however, clinical details were limited (Chmara M et al. J Appl Genet, 2010;51:95-106; Martín-Campos JM et al. J Clin Lipidol, 2018 Sep;12:1452-1462). This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Dec 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV005201887.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Identified in two unrelated individuals with familial hypercholesterolemia (FH) in the published literature (PMID: 20145306, 30293936); In silico analysis suggests this variant may impact gene … (more)
Identified in two unrelated individuals with familial hypercholesterolemia (FH) in the published literature (PMID: 20145306, 30293936); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 32719484, 22881376, 34426522, 30293936, 20145306) (less)
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Uncertain significance
(Jul 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361868.3
First in ClinVar: Jun 22, 2020 Last updated: Sep 16, 2024 |
Comment:
Variant summary: LDLR c.1503G>A alters a conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Four predict … (more)
Variant summary: LDLR c.1503G>A alters a conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.2e-05 in 251456 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1503G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Chmara 2010, Martin-Campos 2018, Latkovskis_2023). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. 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: 20145306, 22881376, 30293936, 32719484, 37568561). ClinVar contains an entry for this variant (Variation ID: 251876). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001923080.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001975937.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Uncertain significance
(Feb 19, 2020)
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no assertion criteria provided
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002086428.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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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Genetic Characteristics of Latvian Patients with Familial Hypercholesterolemia: The First Analysis from Genome-Wide Sequencing. | Latkovskis G | Journal of clinical medicine | 2023 | PMID: 37568561 |
Population genetic screening efficiently identifies carriers of autosomal dominant diseases. | Grzymski JJ | Nature medicine | 2020 | PMID: 32719484 |
Autosomal dominant hypercholesterolemia in Catalonia: Correspondence between clinical-biochemical and genetic diagnostics in 967 patients studied in a multicenter clinical setting. | Martín-Campos JM | Journal of clinical lipidology | 2018 | PMID: 30293936 |
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 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7eefa188-b416-4524-a682-6645dee9f628 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/b3dab714-f339-4ec9-97ce-dadeada970af | - | - | - | - |
Text-mined citations for rs368889457 ...
HelpRecord last updated Sep 29, 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.