0/190 non-FH alleles
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.939C>A (p.Cys313Ter)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic
9 out of 10 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.
10
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000527.5(LDLR):c.939C>A (p.Cys313Ter)
Variation ID: 251539 Accession: VCV000251539.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11107513 (GRCh38) [ NCBI UCSC ] 19: 11218189 (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 Oct 15, 2016 Apr 13, 2025 Aug 17, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.939C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Cys313Ter nonsense NM_001195798.2:c.939C>A NP_001182727.1:p.Cys313Ter nonsense NM_001195799.2:c.816C>A NP_001182728.1:p.Cys272Ter nonsense NM_001195800.2:c.435C>A NP_001182729.1:p.Cys145Ter nonsense NM_001195803.2:c.558C>A NP_001182732.1:p.Cys186Ter nonsense NC_000019.10:g.11107513C>A NC_000019.9:g.11218189C>A NG_009060.1:g.23133C>A LRG_274:g.23133C>A LRG_274t1:c.939C>A LRG_274p1:p.Cys313Ter - Protein change
- C313*, C272*, C186*, C145*
- Other names
- -
- Canonical SPDI
- NC_000019.10:11107512:C:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| LDLR | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4261 | 4568 | |
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 (7) |
criteria provided, multiple submitters, no conflicts
|
Mar 15, 2022 | RCV000237235.11 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 17, 2023 | RCV000775228.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 29, 2022 | RCV002446475.2 |
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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|---|---|---|---|---|---|
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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: SCV000295073.2
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
Observation 4:
Number of individuals with the variant: 1
|
|
|
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: SCV000322920.1
First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016 |
Comment:
0/190 non-FH alleles
Observation 1: Observation 2:
Comment on evidence:
Homozygous patients' fibroblasts, 125I-LDL assays
Result:
<1% / <2% LDLR activity
|
|
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Pathogenic
(Nov 05, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
inherited
|
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation
Additional submitter:
Centre of Molecular Biology and Gene Therapy, University Hospital Brno
Accession: SCV000540772.2
First in ClinVar: Oct 15, 2016 Last updated: Apr 13, 2025 |
Number of individuals with the variant: 8
Clinical Features:
Hypercholesterolemia (present) , Xanthelasma (present)
Zygosity: Single Heterozygote
Family history: yes
Age: 5-53 years
Sex: mixed
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Tissue: Whole blood
|
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Pathogenic
(Mar 30, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Familial Hypercholesterolemia
Affected status: yes
Allele origin:
germline
|
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille
Accession: SCV000583764.1
First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016
Comment:
ACMG Guidelines: Pathogenic (i)
|
Number of individuals with the variant: 1
Clinical Features:
Hyperbetalipoproteinemia (present) , Hypercholesterolemia (present)
Comment on clinical features:
"Dutch Lipid Clinic" Diagnostic Scoring ESC/EAS Guidelines 2016 - PMID: 27567407
Indication for testing: Familial Hypercholesterolemia
Geographic origin: France
Comment on evidence:
Dutch Lipid Clinic Scoring : Probable FH
Secondary finding: no
|
|
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Pathogenic
(Mar 23, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemias
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000909479.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
Comment:
Pathogenic variant based on current evidence: This variant (also known as C292X and FH-Cyprus) changes one nucleotide in exon 6 of the LDLR gene. This … (more)
Pathogenic variant based on current evidence: This variant (also known as C292X and FH-Cyprus) changes one nucleotide in exon 6 of the LDLR gene. This creates a premature translational stop signal and is expected to result in an absent or non-functional protein product. Truncating variants in LDLR are known to be pathogenic (PMID: 20809525). While this variant is rare in the general population (0/277264 chromosomes in the Genome Aggregation Database (gnomAD)), it has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 1301956, 17142622, 21310417, 22698793). Based on available evidence, this variant is classified as Pathogenic. (less)
|
|
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Pathogenic
(Jun 04, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: research
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia
Accession: SCV001432673.1
First in ClinVar: Sep 19, 2020 Last updated: Sep 19, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
Comment on clinical features:
20 (clinical Dutch Lipid Clinic Network Criteria score); 8.16 mmol/L (calculated low-density lipoprotein cholesterol level)
|
|
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Pathogenic
(Aug 29, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002682440.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.C313* pathogenic mutation (also known as c.939C>A), located in coding exon 6 of the LDLR gene, results from a C to A substitution at … (more)
The p.C313* pathogenic mutation (also known as c.939C>A), located in coding exon 6 of the LDLR gene, results from a C to A substitution at nucleotide position 939. This changes the amino acid from a cysteine to a stop codon within coding exon 6. This variant (also referred to as p.C292* and FH Cyprus) has been detected in individuals from numerous familial hypercholesterolemia (FH) cohorts of various ethnic backgrounds, including a homozygous occurrence and co-occurrence with a PCSK9 variant in individuals with features consistent with homozygous FH (Leren TP et al. Atherosclerosis, 2021 04;322:61-66; Hori M et al. Atherosclerosis, 2019 10;289:101-108; Saracoglu E et al. Echocardiography, 2018 09;35:1289-1299; Tichý L et al. Atherosclerosis, 2012 Aug;223:401-8; Noguchi T et al. Atherosclerosis, 2010 May;210:166-72; Glynou K et al. Clin Biochem, 2008 Mar;41:335-42; Humphries SE et al. J Med Genet, 2006 Dec;43:943-9; Xenophontos SL et al. Hum Mutat, 2000 Apr;15:380; Webb JC et al. J Lipid Res, 1996 Feb;37:368-81). Assays performed on patient cells homozygous for this variant indicated significantly reduced LDL-R activity (Webb JC et al. J Lipid Res, 1996 Feb;37:368-81). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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
(Mar 15, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003819498.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Aug 17, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004298339.2
First in ClinVar: Feb 14, 2024 Last updated: Mar 04, 2025 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 251539). 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: 251539). This variant is also known as FH Cyprus, Cys292Ter, and C292X. This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 1301956, 10737984, 30241732, 31491741). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys313*) 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
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: research
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Accession: SCV000606275.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
|
Comment:
Comment:
Pathogenic variant based on current evidence: This variant (also known as C292X and FH-Cyprus) changes one nucleotide in exon 6 of the LDLR gene. This creates a premature translational stop signal and is expected to result in an absent or non-functional protein product. Truncating variants in LDLR are known to be pathogenic (PMID: 20809525). While this variant is rare in the general population (0/277264 chromosomes in the Genome Aggregation Database (gnomAD)), it has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 1301956, 17142622, 21310417, 22698793). Based on available evidence, this variant is classified as Pathogenic.
Comment:
The p.C313* pathogenic mutation (also known as c.939C>A), located in coding exon 6 of the LDLR gene, results from a C to A substitution at nucleotide position 939. This changes the amino acid from a cysteine to a stop codon within coding exon 6. This variant (also referred to as p.C292* and FH Cyprus) has been detected in individuals from numerous familial hypercholesterolemia (FH) cohorts of various ethnic backgrounds, including a homozygous occurrence and co-occurrence with a PCSK9 variant in individuals with features consistent with homozygous FH (Leren TP et al. Atherosclerosis, 2021 04;322:61-66; Hori M et al. Atherosclerosis, 2019 10;289:101-108; Saracoglu E et al. Echocardiography, 2018 09;35:1289-1299; Tichý L et al. Atherosclerosis, 2012 Aug;223:401-8; Noguchi T et al. Atherosclerosis, 2010 May;210:166-72; Glynou K et al. Clin Biochem, 2008 Mar;41:335-42; Humphries SE et al. J Med Genet, 2006 Dec;43:943-9; Xenophontos SL et al. Hum Mutat, 2000 Apr;15:380; Webb JC et al. J Lipid Res, 1996 Feb;37:368-81). Assays performed on patient cells homozygous for this variant indicated significantly reduced LDL-R activity (Webb JC et al. J Lipid Res, 1996 Feb;37:368-81). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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: 251539). This variant is also known as FH Cyprus, Cys292Ter, and C292X. This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 1301956, 10737984, 30241732, 31491741). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys313*) 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:
Pathogenic variant based on current evidence: This variant (also known as C292X and FH-Cyprus) changes one nucleotide in exon 6 of the LDLR gene. This creates a premature translational stop signal and is expected to result in an absent or non-functional protein product. Truncating variants in LDLR are known to be pathogenic (PMID: 20809525). While this variant is rare in the general population (0/277264 chromosomes in the Genome Aggregation Database (gnomAD)), it has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 1301956, 17142622, 21310417, 22698793). Based on available evidence, this variant is classified as Pathogenic.
Comment:
The p.C313* pathogenic mutation (also known as c.939C>A), located in coding exon 6 of the LDLR gene, results from a C to A substitution at nucleotide position 939. This changes the amino acid from a cysteine to a stop codon within coding exon 6. This variant (also referred to as p.C292* and FH Cyprus) has been detected in individuals from numerous familial hypercholesterolemia (FH) cohorts of various ethnic backgrounds, including a homozygous occurrence and co-occurrence with a PCSK9 variant in individuals with features consistent with homozygous FH (Leren TP et al. Atherosclerosis, 2021 04;322:61-66; Hori M et al. Atherosclerosis, 2019 10;289:101-108; Saracoglu E et al. Echocardiography, 2018 09;35:1289-1299; Tichý L et al. Atherosclerosis, 2012 Aug;223:401-8; Noguchi T et al. Atherosclerosis, 2010 May;210:166-72; Glynou K et al. Clin Biochem, 2008 Mar;41:335-42; Humphries SE et al. J Med Genet, 2006 Dec;43:943-9; Xenophontos SL et al. Hum Mutat, 2000 Apr;15:380; Webb JC et al. J Lipid Res, 1996 Feb;37:368-81). Assays performed on patient cells homozygous for this variant indicated significantly reduced LDL-R activity (Webb JC et al. J Lipid Res, 1996 Feb;37:368-81). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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: 251539). This variant is also known as FH Cyprus, Cys292Ter, and C292X. This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 1301956, 10737984, 30241732, 31491741). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys313*) 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 |
|---|---|---|---|---|
| Molecular genetic testing for autosomal dominant hypercholesterolemia in 29,449 Norwegian index patients and 14,230 relatives during the years 1993-2020. | Leren TP | Atherosclerosis | 2021 | PMID: 33740630 |
| A catalog of the pathogenic mutations of LDL receptor gene in Japanese familial hypercholesterolemia. | Tada H | Journal of clinical lipidology | 2020 | PMID: 32331935 |
| Impact of LDLR and PCSK9 pathogenic variants in Japanese heterozygous familial hypercholesterolemia patients. | Hori M | Atherosclerosis | 2019 | PMID: 31491741 |
| Oligogenic familial hypercholesterolemia, LDL cholesterol, and coronary artery disease. | Tada H | Journal of clinical lipidology | 2018 | PMID: 30241732 |
| Prediction of subtle left ventricular systolic dysfunction in homozygous and heterozygous familial hypercholesterolemia: Genetic analyses and speckle tracking echocardiography study. | Saracoglu E | Echocardiography (Mount Kisco, N.Y.) | 2018 | PMID: 29870584 |
| Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene. | Jiang L | Atherosclerosis | 2017 | PMID: 28645073 |
| The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations. | Tichý L | Atherosclerosis | 2012 | PMID: 22698793 |
| An APEX-based genotyping microarray for the screening of 168 mutations associated with familial hypercholesterolemia. | Dušková L | Atherosclerosis | 2011 | PMID: 21310417 |
| Molecular spectrum of autosomal dominant hypercholesterolemia in France. | Marduel M | Human mutation | 2010 | PMID: 20809525 |
| The E32K variant of PCSK9 exacerbates the phenotype of familial hypercholesterolaemia by increasing PCSK9 function and concentration in the circulation. | Noguchi T | Atherosclerosis | 2010 | PMID: 20006333 |
| Development of a universal chemiluminometric genotyping method for high-throughput detection of 7 LDLR gene mutations in Greek population. | Glynou K | Clinical biochemistry | 2008 | PMID: 18206115 |
| Genetic defects causing familial hypercholesterolaemia: identification of deletions and duplications in the LDL-receptor gene and summary of all mutations found in patients attending the Hammersmith Hospital Lipid Clinic. | Tosi I | Atherosclerosis | 2007 | PMID: 17094996 |
| Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk. | Humphries SE | Journal of medical genetics | 2006 | PMID: 17142622 |
| LDL-receptor mutations in Europe. | Dedoussis GV | Human mutation | 2004 | PMID: 15523646 |
| Application of molecular genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program. | Leren TP | Seminars in vascular medicine | 2004 | PMID: 15199436 |
| Geographical clustering of low density lipoprotein receptor gene mutations (C292X; Q363X; D365E & C660X) in Cyprus. | Xenophontos SL | Human mutation | 2000 | PMID: 10737984 |
| Characterization of mutations in the low density lipoprotein (LDL)-receptor gene in patients with homozygous familial hypercholesterolemia, and frequency of these mutations in FH patients in the United Kingdom. | Webb JC | Journal of lipid research | 1996 | PMID: 9026534 |
| Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. | Hobbs HH | Human mutation | 1992 | PMID: 1301956 |
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Text-mined citations for rs13306512 ...
HelpThese citations are identified by LitVar using
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 Apr 13, 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.