ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1359-5C>G
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000527.5(LDLR):c.1359-5C>G
Variation ID: 251808 Accession: VCV000251808.32
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.2 19: 11113530 (GRCh38) [ NCBI UCSC ] 19: 11224206 (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 Aug 11, 2024 Aug 27, 2022 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000527.5:c.1359-5C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001195798.2:c.1359-5C>G intron variant NM_001195799.2:c.1236-5C>G intron variant NM_001195800.2:c.855-5C>G intron variant NM_001195803.2:c.978-5C>G intron variant NR_106946.1:n.57C>G non-coding transcript variant NC_000019.10:g.11113530C>G NC_000019.9:g.11224206C>G NG_009060.1:g.29150C>G LRG_274:g.29150C>G LRG_274t1:c.1359-5C>G - Protein change
- Other names
- -
- Canonical SPDI
- NC_000019.10:11113529:C:G
-
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.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
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 |
4059 | 4334 | |
MIR6886 | - | - | - | GRCh38 | - | 53 |
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. |
---|---|---|---|---|
Likely pathogenic (8) |
reviewed by expert panel
|
Aug 27, 2022 | RCV000238316.15 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Jan 27, 2021 | RCV000844742.5 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Oct 31, 2023 | RCV001052016.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Jun 20, 2023 | RCV001568174.7 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
May 8, 2024 | RCV004639193.1 |
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
(Aug 27, 2022)
|
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: SCV002817175.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
The NM_000527.5(LDLR):c.1359-5C>G variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_moderate, PM2, PP4, PS3_supporting, PS4_supporting) as defined by the ClinGen … (more)
The NM_000527.5(LDLR):c.1359-5C>G variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_moderate, PM2, PP4, PS3_supporting, PS4_supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PP1_moderate: Variant segregates with FH phenotype in 4 informative meioses in 1 family from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge PM2: PopMax MAF = 0.00001766 (0.001766%) in European (non-Finnish) population exomes (gnomAD v2.1.1). PP3: No REVEL, splicing evaluation required. Functional data on splicing not available. A) variant located at -20 to +3 bases from canonical acceptor splice site, MES scores: canonical site variant = 4.09; canonical acceptor wt = 6.76. Ratio variant/wt canonical acceptor: 4.09/6.76 = 0.605 ---- It is below 0.8 Variant is predicted to alter splicing. PP4: Variant meets PM2 and is identified in at least 3 index cases (1 index from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge who meets the Simon Broome Possible criteria; 1 case with Simon-Broome criteria of possible FH in PMID: 19411563, and 1 case with Simon-Broome criteria of possible FH in PMID: 30876530), after alternative causes of high cholesterol were excluded PS3_supporting: Level 3 assay: PMID 19411563: Heterozygous patients' lymphocytes, RNA assays - result - Retention of intron 9 (p.Ser453Argfs*2) ---- functional study is consistent with damaging effect. PS4_supporting: Variant meets PM2 and is identified in 3 index cases (1 index from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge who meets the Simon Broome Possible criteria; 1 case with Simon-Broome criteria of possible FH in PMID: 19411563, and 1 case with Simon-Broome criteria of possible FH in PMID: 30876530). (less)
|
|
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: SCV000295389.2
First in ClinVar: Jul 29, 2016 Last updated: Apr 09, 2018 |
Number of individuals with the variant: 1
|
|
Uncertain significance
(Mar 01, 2016)
|
criteria provided, single submitter
Method: research
|
Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
|
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
Accession: SCV000322946.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
0/75 normolipidaemic Portuguese controls
Observation 1: Observation 2:
Comment on evidence:
Heterozygous patients' lymphocytes, RNA assays
Result:
Retention of intron 9 (p.Ser453Argfs*2)
|
|
Uncertain significance
(Oct 12, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001286369.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
Uncertain significance
(Jan 27, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000731830.3
First in ClinVar: Apr 09, 2018 Last updated: May 29, 2021 |
Comment:
Variant classified as Uncertain Significance - Favor Pathogenic. The c.1359-5G>C variant in LDLR has been reported in 2 Portuguese individuals with Familial hypercholesterolemia (FH) and … (more)
Variant classified as Uncertain Significance - Favor Pathogenic. The c.1359-5G>C variant in LDLR has been reported in 2 Portuguese individuals with Familial hypercholesterolemia (FH) and segregated with disease in 2 affected individuals from 2 families, although in at least 1 of the families segregation was incomplete and 2 affected individuals were not carriers of this variant (Bourbon 2009 PMID: 19411563, Medeiros 2014 PMID:24627126, Gaspar 2019 PMID: 30876530). It has also been identified in 0.002% (2/113226) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 251808). This variant is located in the 3' splice region. Computational tools do not predict a splicing impact, though this information is not predictive enough to rule out pathogenicity. Amplification of patient mRNA by RT-PCR has shown that this variant causes retention of intron 9 and is predicted to result in a frameshift, which alters the protein's amino acid sequence beginning at position 453 and leads to a premature termination codon 1 amino acid downstream (Bourbon 2009 PMID: 19411563). This alteration is then predicted to lead to a truncated or absent protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PS3_Supporting, PS4_Supporting. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002516651.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
|
|
Uncertain significance
(Sep 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001216204.3
First in ClinVar: Apr 15, 2020 Last updated: Feb 07, 2023 |
Comment:
This sequence change falls in intron 9 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. … (more)
This sequence change falls in intron 9 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs531005522, gnomAD 0.002%). This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 19411563, 24627126). ClinVar contains an entry for this variant (Variation ID: 251808). Studies have shown that this variant results in intron 9 inclusion and introduces a premature termination codon (PMID: 19411563). The resulting mRNA is expected to undergo nonsense-mediated decay. 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)
|
|
Likely pathogenic
(Jun 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001791999.5
First in ClinVar: Aug 19, 2021 Last updated: Jul 01, 2023 |
Comment:
Published functional studies of patient cDNA showed that the c.1359-5 C>G variant results in an abnormally spliced protein that includes intron 9, and that intron … (more)
Published functional studies of patient cDNA showed that the c.1359-5 C>G variant results in an abnormally spliced protein that includes intron 9, and that intron 9 contains an in-frame stop codon resulting in a transcript with premature termination (Bourbon et al., 2009); however, wild type mRNA appears to be expressed at a higher level than variant mRNA, suggesting the c.1359-5 C>G variant may not result in a complete null allele (Bourbon et al., 2009); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20828696, 22881376, 20964105, 24075752, 30876530, 27821657, 24627126, 31447099, 19411563, 32719484) (less)
|
|
Uncertain significance
(Nov 16, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003816525.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
Likely pathogenic
(Oct 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001347905.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant causes a C>G nucleotide substitution at the -5 position of intron 9 of the LDLR gene. A transcriptional study using RNA from a … (more)
This variant causes a C>G nucleotide substitution at the -5 position of intron 9 of the LDLR gene. A transcriptional study using RNA from a heterozygous carrier individual has shown that this variant causes a retention of intron 9 and results in a frameshift and premature protein truncation (PMID: 19411563). This variant has been reported in four individuals affected with familial hypercholesterolemia from two unrelated families (PMID: 19411563, 24627126). One affected individual from one of these families was not a carrier (PMID: 19411563). It has been shown that this variant segregates with disease in multiple affected individuals across two families (PMID: 19411563, 24627126; ClinVar SCV000322946.1). This variant has also been reported in one individual affected with myocardial infarction (PMID: 30876530). This variant has been identified in 3/250802 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
|
|
Likely Pathogenic
(Nov 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004830207.1
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)
|
Comment:
The c.1359-5C>G variant of the LDLR gene has been identified in a family with familial hypercholesterolemia (FH). mRNA study from patient cells revealed retention of … (more)
The c.1359-5C>G variant of the LDLR gene has been identified in a family with familial hypercholesterolemia (FH). mRNA study from patient cells revealed retention of intron 9, resulting in a frame shift and premature truncation of the protein (PMID: 19411563, 17765246). Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 21310417). In addition, the variant has been identified in 3 index cases and segregates with FH phenotype in 4 informative meiosis from different laboratories according to ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel. The variant has been reported in ClinVar as likely pathogenic and reviewed by the expert panel (ClinVar: 251808). The variant is rare in the general population according to gnomAD (3/250802). Therefore, the c.1359-5C>G variant of LDLR has been classified as likely pathogenic. (less)
Number of individuals with the variant: 7
|
|
Likely pathogenic
(Jul 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
inherited
|
New York Genome Center
Study: PrenatalSEQ
Accession: SCV005044090.1 First in ClinVar: May 19, 2024 Last updated: May 19, 2024 |
Comment:
The inherited c.1359-5C>G variant identified in the LDLR gene is an intronic variant at the -5 position within intron 9/17. This variant is found with … (more)
The inherited c.1359-5C>G variant identified in the LDLR gene is an intronic variant at the -5 position within intron 9/17. This variant is found with low frequency in population databases (allele frequency=3.80e-5; gnomADv2.1.1, gnomADv3.1.2, BRAVO-TOPMed, All of Us) suggesting it is not a common benign variant in the populations represented in those databases. This variant has been curated by the Hypercholesterolemia Variant Curation Expert Panel of the Clinical Genome Resource (ClinGen) and deposited in ClinVar as Likely Pathogenic (VarID:251808). This variant has been reported in many affected individuals in the literature [PMID:19411563, 24627126, 30876530, others], and functional studies demonstrate this variant leads to the retention of nucleotide sequences within intron 9 and is predicted to lead to a frameshift (p.(Ser453Argfs*2)) [PMID:19411563]. Given the available evidence, the paternally inherited c.1359-5C>G variant identified in the LDLR gene of this fetus is reported here as Likely Pathogenic (less)
Clinical Features:
Spina bifida (present) , Neural tube defect (present) , Mild fetal ventriculomegaly (present) , Corpus callosum, agenesis of (present) , Lobar holoprosencephaly (present)
Age: 20-29 weeks gestation
Secondary finding: yes
|
|
Likely pathogenic
(May 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV005136001.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
The c.1359-5C>G intronic variant results from a C to G substitution 5 nucleotides upstream from coding exon 10 in the LDLR gene. This variant has … (more)
The c.1359-5C>G intronic variant results from a C to G substitution 5 nucleotides upstream from coding exon 10 in the LDLR gene. This variant has been detected in individuals with features consistent with familial hypercholesterolemia and has been reported to segregate with disease in families; however, in one family, segregation data was unclear (Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42; Medeiros AM et al. J. Lipid Res., 2014 May;55:947-55). RNA studies by one group indicate that this variant causes retention of intron 9, leading to incorporation of a stop codon (Bourbon M et al. J. Med. Genet., 2009 May;46:352-7). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Variable expression and penetrance in Portuguese families with Familial Hypercholesterolemia with mild phenotype. | Gaspar IM | Atherosclerosis. Supplements | 2019 | PMID: 30876530 |
The UCL low-density lipoprotein receptor gene variant database: pathogenicity update. | Leigh S | Journal of medical genetics | 2017 | PMID: 27821657 |
Cardiovascular risk assessment of dyslipidemic children: analysis of biomarkers to identify monogenic dyslipidemia. | Medeiros AM | Journal of lipid research | 2014 | PMID: 24627126 |
Detection of variations and identifying genomic breakpoints for large deletions in the LDLR by Ion Torrent semiconductor sequencing. | Faiz F | Atherosclerosis | 2013 | PMID: 24075752 |
Low-density lipoprotein receptor gene familial hypercholesterolemia variant database: update and pathological assessment. | Usifo E | Annals of human genetics | 2012 | PMID: 22881376 |
An APEX-based genotyping microarray for the screening of 168 mutations associated with familial hypercholesterolemia. | Dušková L | Atherosclerosis | 2011 | PMID: 21310417 |
Molecular diagnosis of familial hypercholesterolemia: an important tool for cardiovascular risk stratification. | Alves AC | Revista portuguesa de cardiologia : orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology | 2010 | PMID: 20964105 |
Update of the Portuguese Familial Hypercholesterolaemia Study. | Medeiros AM | Atherosclerosis | 2010 | PMID: 20828696 |
Molecular spectrum of autosomal dominant hypercholesterolemia in France. | Marduel M | Human mutation | 2010 | PMID: 20809525 |
Genetic diagnosis of familial hypercholesterolaemia: the importance of functional analysis of potential splice-site mutations. | Bourbon M | Journal of medical genetics | 2009 | PMID: 19411563 |
Familial hypercholesterolaemia in Portugal. | Bourbon M | Atherosclerosis | 2008 | PMID: 17765246 |
Hunger and satiety in man. | Hashim SA | Current concepts in nutrition | 1977 | PMID: 322946 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/73216f9d-b472-44cf-a82f-136037e4541b | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs531005522 ...
HelpRecord last updated Sep 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.