0/190 non-FH alleles
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1033C>T (p.Gln345Ter)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic
7 out of 9 submissions contributed to this 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
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.1033C>T (p.Gln345Ter)
Variation ID: 226341 Accession: VCV000226341.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11110744 (GRCh38) [ NCBI UCSC ] 19: 11221420 (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 Feb 25, 2025 Jul 17, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.1033C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Gln345Ter nonsense NM_001195798.2:c.1033C>T NP_001182727.1:p.Gln345Ter nonsense NM_001195799.2:c.910C>T NP_001182728.1:p.Gln304Ter nonsense NM_001195800.2:c.529C>T NP_001182729.1:p.Gln177Ter nonsense NM_001195803.2:c.652C>T NP_001182732.1:p.Gln218Ter nonsense NC_000019.10:g.11110744C>T NC_000019.9:g.11221420C>T NG_009060.1:g.26364C>T LRG_274:g.26364C>T LRG_274t1:c.1033C>T LRG_274p1:p.Gln345Ter - Protein change
- Q345*, Q218*, Q304*, Q177*
- Other names
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- Canonical SPDI
- NC_000019.10:11110743:C:T
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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 |
4216 | 4517 | |
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 (6) |
criteria provided, multiple submitters, no conflicts
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Dec 16, 2016 | RCV000211644.9 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 17, 2023 | RCV001260435.5 | |
| Pathogenic (1) |
criteria provided, single submitter
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Aug 19, 2022 | RCV002390566.2 |
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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Pathogenic
(Mar 25, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: literature only
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
LDLR-LOVD, British Heart Foundation
Accession: SCV000295153.2
First in ClinVar: Jul 29, 2016 Last updated: Sep 30, 2017 |
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)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: research
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
Accession: SCV000322923.1
First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016 |
Comment:
0/190 non-FH alleles
Observation 1: Observation 2: |
|
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Pathogenic
(Dec 16, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
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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: SCV000503284.1
First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016 |
Comment:
subjects mutated among 2600 FH index cases screened = 3 , family member = 1 with co-segregation / previously described in association with FH
Number of individuals with the variant: 3
|
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Pathogenic
(Mar 01, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: research
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Study: HipercolBrasil
Accession: SCV000588542.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017 |
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Pathogenic
(Sep 16, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001437432.1
First in ClinVar: Oct 08, 2020 Last updated: Oct 08, 2020 |
Comment:
Variant summary: LDLR c.1033C>T (p.Gln345X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: LDLR c.1033C>T (p.Gln345X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251072 control chromosomes (gnomAD). c.1033C>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Day_1997, Bourbon_2008, Hooper_2012). 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. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Aug 19, 2022)
C
Contributing to aggregate classification
|
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: SCV002699179.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.Q345* pathogenic mutation (also known as c.1033C>T), located in coding exon 7 of the LDLR gene, results from a C to T substitution at … (more)
The p.Q345* pathogenic mutation (also known as c.1033C>T), located in coding exon 7 of the LDLR gene, results from a C to T substitution at nucleotide position 1033. This changes the amino acid from a glutamine to a stop codon within coding exon 7. This alteration, which is also known as p.Q324*, has been reported in individuals with familial hypercholesterolemia (FH) (Day IN et al. Hum Mutat, 1997;10:116-27; Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42; Taylor A et al. Clin Genet, 2010 Jun;77:572-80; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
|
|
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Pathogenic
(Jul 17, 2023)
C
Contributing to aggregate classification
|
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: SCV003443871.3
First in ClinVar: Feb 07, 2023 Last updated: Feb 25, 2025 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 226341). This variant is also known … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 226341). This variant is also known as Q324X. This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 9259195). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln345*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). (less)
|
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Pathogenic
(Jul 22, 2008)
N
Not contributing to aggregate classification
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no assertion criteria provided
Method: clinical testing
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Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
|
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital
Accession: SCV000268594.1
First in ClinVar: May 22, 2016 Last updated: May 22, 2016 |
Number of individuals with the variant: 2
|
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Pathogenic
(-)
N
Not contributing to aggregate classification
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no assertion criteria provided
Method: research
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Accession: SCV000606297.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
Comment:
Comment:
subjects mutated among 2600 FH index cases screened = 3 , family member = 1 with co-segregation / previously described in association with FH
Comment:
Variant summary: LDLR c.1033C>T (p.Gln345X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251072 control chromosomes (gnomAD). c.1033C>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Day_1997, Bourbon_2008, Hooper_2012). 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. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The p.Q345* pathogenic mutation (also known as c.1033C>T), located in coding exon 7 of the LDLR gene, results from a C to T substitution at nucleotide position 1033. This changes the amino acid from a glutamine to a stop codon within coding exon 7. This alteration, which is also known as p.Q324*, has been reported in individuals with familial hypercholesterolemia (FH) (Day IN et al. Hum Mutat, 1997;10:116-27; Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42; Taylor A et al. Clin Genet, 2010 Jun;77:572-80; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 226341). This variant is also known as Q324X. This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 9259195). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln345*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073).
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:
0/190 non-FH alleles
Comment:
subjects mutated among 2600 FH index cases screened = 3 , family member = 1 with co-segregation / previously described in association with FH
Comment:
Variant summary: LDLR c.1033C>T (p.Gln345X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251072 control chromosomes (gnomAD). c.1033C>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Day_1997, Bourbon_2008, Hooper_2012). 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. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The p.Q345* pathogenic mutation (also known as c.1033C>T), located in coding exon 7 of the LDLR gene, results from a C to T substitution at nucleotide position 1033. This changes the amino acid from a glutamine to a stop codon within coding exon 7. This alteration, which is also known as p.Q324*, has been reported in individuals with familial hypercholesterolemia (FH) (Day IN et al. Hum Mutat, 1997;10:116-27; Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42; Taylor A et al. Clin Genet, 2010 Jun;77:572-80; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 226341). This variant is also known as Q324X. This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 9259195). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln345*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene. | Jiang L | Atherosclerosis | 2017 | PMID: 28645073 |
| Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. | Bertolini S | Atherosclerosis | 2013 | PMID: 23375686 |
| 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 |
| Mutation detection rate and spectrum in familial hypercholesterolaemia patients in the UK pilot cascade project. | Taylor A | Clinical genetics | 2010 | PMID: 20236128 |
| Familial hypercholesterolaemia in Portugal. | Bourbon M | Atherosclerosis | 2008 | PMID: 17765246 |
| Spectrum of LDL receptor gene mutations in heterozygous familial hypercholesterolemia. | Day IN | Human mutation | 1997 | PMID: 9259195 |
Text-mined citations for this variant ...
HelpRecord last updated Feb 26, 2025
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.