The c.1705+1G>A variant in the LDLR gene disrupts the canonical splice donor site in intron 11 and is predicted to result in abnormal mRNA splicing. This variant has been reported in multiple unrelated individuals with familial hypercholesterolemia (PMID: 10532689, 19318025, 20145306). The c.1705+1G>A variant in the LDLR gene is classified as likely pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1705+1G>A
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(9)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000527.5(LDLR):c.1705+1G>A
Variation ID: 226367 Accession: VCV000226367.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11116213 (GRCh38) [ NCBI UCSC ] 19: 11226889 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 22, 2016 May 1, 2024 Nov 15, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.1705+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001195798.2:c.1705+1G>A splice donor NM_001195799.2:c.1582+1G>A splice donor NM_001195800.2:c.1201+1G>A splice donor NM_001195803.2:c.1324+1G>A splice donor NC_000019.10:g.11116213G>A NC_000019.9:g.11226889G>A NG_009060.1:g.31833G>A LRG_274:g.31833G>A LRG_274t1:c.1705+1G>A - Protein change
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- Other names
- -
- Canonical SPDI
- NC_000019.10:11116212: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
Help
The frequency of the allele represented by this VCV record.
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- 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. |
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| LDLR | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4075 | 4351 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Mar 27, 2018 | RCV000211580.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 11, 2018 | RCV000825623.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 23, 2019 | RCV001034672.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 26, 2019 | RCV002408917.2 | |
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LDLR-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Nov 15, 2022 | RCV003417769.4 |
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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|---|---|---|---|---|---|
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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: SCV000295591.2
First in ClinVar: Jul 29, 2016 Last updated: Oct 10, 2018 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
Observation 3:
Number of individuals with the variant: 1
|
|
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Pathogenic
(Mar 01, 2016)
|
criteria provided, single submitter
Method: curation, literature only
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown, not applicable
Allele origin:
germline,
not applicable
|
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
Accession: SCV000599381.1
First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017 |
Observation 1: Observation 2:
Comment on evidence:
Assay Description:Htz patients' Epstein Barr virus transformed lymphocytes, RNA assays
Result:
skipping of exon 11 (p.Phe530Serfs*10) or 11 and 12 (p.Phe530Thrfs*49), mutant mRNA degraded (~15% of total)
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Pathogenic
(Mar 01, 2016)
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criteria provided, single submitter
Method: research
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Iberoamerican FH Network
Accession: SCV000748114.1
First in ClinVar: May 19, 2018 Last updated: May 19, 2018
Comment:
Variant present in the database from Chile
|
Observation 1: Observation 2:
Comment on evidence:
Assay Description: Htz patients' Epstein Barr virus transformed lymphocytes, RNA assays
Result:
skipping of exon 11 (p.Phe530Serfs*10) or 11 and 12 (p.Phe530Thrfs*49), mutant mRNA degraded (~15% of total)
|
|
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Likely pathogenic
(Mar 27, 2018)
|
criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV000839976.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
Comment:
The c.1705+1G>A variant in the LDLR gene disrupts the canonical splice donor site in intron 11 and is predicted to result in abnormal mRNA splicing. … (more)
The c.1705+1G>A variant in the LDLR gene disrupts the canonical splice donor site in intron 11 and is predicted to result in abnormal mRNA splicing. This variant has been reported in multiple unrelated individuals with familial hypercholesterolemia (PMID: 10532689, 19318025, 20145306). The c.1705+1G>A variant in the LDLR gene is classified as likely pathogenic. (less)
|
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Pathogenic
(Jun 11, 2018)
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criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemia - homozygous
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000966975.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
The c.1705+1G>A variant in LDLR has been reported in 6 Caucasian individuals wit h hypercholesterolemia (Jensen 1999, Chmara 2010, Sharifi 2016) and was absent f … (more)
The c.1705+1G>A variant in LDLR has been reported in 6 Caucasian individuals wit h hypercholesterolemia (Jensen 1999, Chmara 2010, Sharifi 2016) and was absent f rom large population studies. This variant occurs in the invariant region (+/- 1 ,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Furthermore, other variants in the sam e splice consensus sequence have been reported in individuals with hypercholeste rolemia (c.1705+1G>C, c.1705+1G>T). In vitro functional studies of the c.1705+1G >T and the c.1705+1G>A variants provide some evidence of abnormal splicing (R?dn ingen 1999; Holla 2009). In summary, this variant meets criteria to be classifie d as pathogenic for hypercholesterolemia in an autosomal dominant manner based u pon proband counts, absence from controls, and functional impact. ACMG/AMP Crite ria applied: PVS1; PM2; PS4_Supporting; PS3_Supporting. (less)
Number of individuals with the variant: 1
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Pathogenic
(Nov 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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LDLR-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004118555.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The LDLR c.1705+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported as pathogenic for … (more)
The LDLR c.1705+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported as pathogenic for autosomal dominant familial hypercholesterolemia (Jensen et al 1999. PubMed ID: 10532689; Table S1, Leren et al 2021. PubMed ID: 33740630; eTable 1, Sturm et al 2021. PubMed ID: 34037665; Chmara et al 2010. PubMed ID: 20145306; Sharifi et al 2015. PubMed ID: 26892515). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in LDLR are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
|
|
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Pathogenic
(Feb 23, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000752424.7
First in ClinVar: May 19, 2018 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: … (more)
For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). Experimental studies have shown that this chance results in exon skipping and in reduced LDLR activity (PMID: 19208450). This variant was observed in individuals affected with familial hypercholesterolemia (PMID: 10532689, 20145306, 19208450, 17406740).   ClinVar contains an entry for this variant (Variation ID: 226367). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 11 of the LDLR gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. (less)
|
|
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Pathogenic
(Sep 26, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002715538.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.1705+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 11 of the LDLR gene. This alteration has … (more)
The c.1705+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 11 of the LDLR gene. This alteration has been detected in several individuals with familial hypercholesterolemia (FH) (Jensen HK et al. Atherosclerosis, 1999 Oct;146:337-44; Chmara M et al. J. Appl. Genet., 2010;51:95-106; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4; Sharifi M et al. Metab. Clin. Exp., 2016 Mar;65:48-53). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. (less)
|
|
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Pathogenic
(Jun 01, 2011)
|
no assertion criteria provided
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
|
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital
Accession: SCV000268630.1
First in ClinVar: May 22, 2016 Last updated: May 22, 2016 |
Number of individuals with the variant: 1
|
Comment:
Comment:
The c.1705+1G>A variant in LDLR has been reported in 6 Caucasian individuals wit h hypercholesterolemia (Jensen 1999, Chmara 2010, Sharifi 2016) and was absent f rom large population studies. This variant occurs in the invariant region (+/- 1 ,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Furthermore, other variants in the sam e splice consensus sequence have been reported in individuals with hypercholeste rolemia (c.1705+1G>C, c.1705+1G>T). In vitro functional studies of the c.1705+1G >T and the c.1705+1G>A variants provide some evidence of abnormal splicing (R?dn ingen 1999; Holla 2009). In summary, this variant meets criteria to be classifie d as pathogenic for hypercholesterolemia in an autosomal dominant manner based u pon proband counts, absence from controls, and functional impact. ACMG/AMP Crite ria applied: PVS1; PM2; PS4_Supporting; PS3_Supporting.
Comment:
The LDLR c.1705+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported as pathogenic for autosomal dominant familial hypercholesterolemia (Jensen et al 1999. PubMed ID: 10532689; Table S1, Leren et al 2021. PubMed ID: 33740630; eTable 1, Sturm et al 2021. PubMed ID: 34037665; Chmara et al 2010. PubMed ID: 20145306; Sharifi et al 2015. PubMed ID: 26892515). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in LDLR are expected to be pathogenic. This variant is interpreted as pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). Experimental studies have shown that this chance results in exon skipping and in reduced LDLR activity (PMID: 19208450). This variant was observed in individuals affected with familial hypercholesterolemia (PMID: 10532689, 20145306, 19208450, 17406740).   ClinVar contains an entry for this variant (Variation ID: 226367). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 11 of the LDLR gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Comment:
The c.1705+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 11 of the LDLR gene. This alteration has been detected in several individuals with familial hypercholesterolemia (FH) (Jensen HK et al. Atherosclerosis, 1999 Oct;146:337-44; Chmara M et al. J. Appl. Genet., 2010;51:95-106; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4; Sharifi M et al. Metab. Clin. Exp., 2016 Mar;65:48-53). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The c.1705+1G>A variant in the LDLR gene disrupts the canonical splice donor site in intron 11 and is predicted to result in abnormal mRNA splicing. This variant has been reported in multiple unrelated individuals with familial hypercholesterolemia (PMID: 10532689, 19318025, 20145306). The c.1705+1G>A variant in the LDLR gene is classified as likely pathogenic.
Comment:
The c.1705+1G>A variant in LDLR has been reported in 6 Caucasian individuals wit h hypercholesterolemia (Jensen 1999, Chmara 2010, Sharifi 2016) and was absent f rom large population studies. This variant occurs in the invariant region (+/- 1 ,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Furthermore, other variants in the sam e splice consensus sequence have been reported in individuals with hypercholeste rolemia (c.1705+1G>C, c.1705+1G>T). In vitro functional studies of the c.1705+1G >T and the c.1705+1G>A variants provide some evidence of abnormal splicing (R?dn ingen 1999; Holla 2009). In summary, this variant meets criteria to be classifie d as pathogenic for hypercholesterolemia in an autosomal dominant manner based u pon proband counts, absence from controls, and functional impact. ACMG/AMP Crite ria applied: PVS1; PM2; PS4_Supporting; PS3_Supporting.
Comment:
The LDLR c.1705+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported as pathogenic for autosomal dominant familial hypercholesterolemia (Jensen et al 1999. PubMed ID: 10532689; Table S1, Leren et al 2021. PubMed ID: 33740630; eTable 1, Sturm et al 2021. PubMed ID: 34037665; Chmara et al 2010. PubMed ID: 20145306; Sharifi et al 2015. PubMed ID: 26892515). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in LDLR are expected to be pathogenic. This variant is interpreted as pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). Experimental studies have shown that this chance results in exon skipping and in reduced LDLR activity (PMID: 19208450). This variant was observed in individuals affected with familial hypercholesterolemia (PMID: 10532689, 20145306, 19208450, 17406740).   ClinVar contains an entry for this variant (Variation ID: 226367). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 11 of the LDLR gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Comment:
The c.1705+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 11 of the LDLR gene. This alteration has been detected in several individuals with familial hypercholesterolemia (FH) (Jensen HK et al. Atherosclerosis, 1999 Oct;146:337-44; Chmara M et al. J. Appl. Genet., 2010;51:95-106; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4; Sharifi M et al. Metab. Clin. Exp., 2016 Mar;65:48-53). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The panorama of familial hypercholesterolemia in Latin America: a systematic review. | Mehta R | Journal of lipid research | 2016 | PMID: 27777316 |
| The genetic spectrum of familial hypercholesterolemia in south-eastern Poland. | Sharifi M | Metabolism: clinical and experimental | 2016 | PMID: 26892515 |
| RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
| Genetic analysis of familial hypercholesterolaemia in Western Australia. | Hooper AJ | Atherosclerosis | 2012 | PMID: 22883975 |
| Molecular spectrum of autosomal dominant hypercholesterolemia in France. | Marduel M | Human mutation | 2010 | PMID: 20809525 |
| Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations. | Chmara M | Journal of applied genetics | 2010 | PMID: 20145306 |
| Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform. | Alonso R | Clinical biochemistry | 2009 | PMID: 19318025 |
| Effects of intronic mutations in the LDLR gene on pre-mRNA splicing: Comparison of wet-lab and bioinformatics analyses. | Holla ØL | Molecular genetics and metabolism | 2009 | PMID: 19208450 |
| [Molecular diagnosis and combined lipid lowering therapy of heterozygous familial hypercholesterolemia. Report of one case]. | Arteaga Ll A | Revista medica de Chile | 2007 | PMID: 17406740 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
| Spectrum of LDL receptor gene mutations in Denmark: implications for molecular diagnostic strategy in heterozygous familial hypercholesterolemia. | Jensen HK | Atherosclerosis | 1999 | PMID: 10532689 |
| Mutant transcripts of the LDL receptor gene: mRNA structure and quantity. | Rødningen OK | Human mutation | 1999 | PMID: 10090473 |
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Text-mined citations for rs875989926 ...
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the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record 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.