subject mutated among 2600 FH index cases screened = 1
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1150C>T (p.Gln384Ter)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic
6 out of 6 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.
6
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000527.5(LDLR):c.1150C>T (p.Gln384Ter)
Variation ID: 251688 Accession: VCV000251688.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11111603 (GRCh38) [ NCBI UCSC ] 19: 11222279 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jul 29, 2016 Feb 25, 2025 Nov 22, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.1150C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Gln384Ter nonsense NM_001195798.2:c.1150C>T NP_001182727.1:p.Gln384Ter nonsense NM_001195799.2:c.1027C>T NP_001182728.1:p.Gln343Ter nonsense NM_001195800.2:c.646C>T NP_001182729.1:p.Gln216Ter nonsense NM_001195803.2:c.769C>T NP_001182732.1:p.Gln257Ter nonsense NC_000019.10:g.11111603C>T NC_000019.9:g.11222279C>T NG_009060.1:g.27223C>T LRG_274:g.27223C>T LRG_274t1:c.1150C>T LRG_274p1:p.Gln384Ter - Protein change
- Q384*, Q216*, Q257*, Q343*
- Other names
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FH Cyprus-2
- Canonical SPDI
- NC_000019.10:11111602: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. |
|||
| LDLR | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4220 | 4521 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 31, 2022 | RCV000237144.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 7, 2024 | RCV004992121.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 22, 2024 | RCV002519845.4 |
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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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: SCV000295245.2
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
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
(Dec 16, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
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: SCV000503304.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
subject mutated among 2600 FH index cases screened = 1
Number of individuals with the variant: 1
|
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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: SCV000583795.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016
Comment:
ACMG Guidelines: Pathogenic (i)
|
Number of individuals with the variant: 2
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
Sex: mixed
Geographic origin: France
Comment on evidence:
Dutch Lipid Clinic Scoring : Definite FH
Secondary finding: no
|
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Pathogenic
(Mar 31, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005399091.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial hypercholesterolemia 1 (MIM#143890) and LDL cholesterol level QTL2 (MIM#143890). (I) 0108 - This gene is associated with both recessive and dominant disease. Biallelic individuals have an earlier and more severe onset (Gene Reviews). (I) 0112 - The condition associated with this gene has incomplete penetrance. Recent findings suggest that only 73% of individuals with a heterozygous LDLR pathogenic variant have elevated LDL levels (GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. Also known as p.(Gln363*) in the literature, this is a Cypriot founder mutation and co-segregates with p.(Asp386Glu) in families with familial hypercholesterolemia (PMID: 27578104). It was noted that in two families, this variant was found in isolation, without the missense variant (PMID: 25463123). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Aug 07, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV005612302.1
First in ClinVar: Jan 13, 2025 Last updated: Jan 13, 2025 |
Comment:
The p.Q384* pathogenic mutation (also known as c.1150C>T), located in coding exon 8 of the LDLR gene, results from a C to T substitution at … (more)
The p.Q384* pathogenic mutation (also known as c.1150C>T), located in coding exon 8 of the LDLR gene, results from a C to T substitution at nucleotide position 1150. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This variant (also referred to as p.Q363*) been detected in individuals with features consistent with familial hypercholesterolemia (Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Dedoussis GV et al. Eur J Clin Invest, 2004 Jun;34:402-9; Dedoussis GV et al. Hum Mutat, 2004 Mar;23:285-6; Humphries SE et al. J Mol Med (Berl), 2006 Mar;84:203-14; Taylor A et al. Clin Genet, 2007 Jun;71:561-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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
(Nov 22, 2024)
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: SCV003443102.3
First in ClinVar: Feb 07, 2023 Last updated: Feb 25, 2025 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln384*) in the LDLR gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gln384*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 19843101, 33740630). ClinVar contains an entry for this variant (Variation ID: 251688). For these reasons, this variant has been classified as Pathogenic. (less)
|
Comment:
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial hypercholesterolemia 1 (MIM#143890) and LDL cholesterol level QTL2 (MIM#143890). (I) 0108 - This gene is associated with both recessive and dominant disease. Biallelic individuals have an earlier and more severe onset (Gene Reviews). (I) 0112 - The condition associated with this gene has incomplete penetrance. Recent findings suggest that only 73% of individuals with a heterozygous LDLR pathogenic variant have elevated LDL levels (GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. Also known as p.(Gln363*) in the literature, this is a Cypriot founder mutation and co-segregates with p.(Asp386Glu) in families with familial hypercholesterolemia (PMID: 27578104). It was noted that in two families, this variant was found in isolation, without the missense variant (PMID: 25463123). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
The p.Q384* pathogenic mutation (also known as c.1150C>T), located in coding exon 8 of the LDLR gene, results from a C to T substitution at nucleotide position 1150. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This variant (also referred to as p.Q363*) been detected in individuals with features consistent with familial hypercholesterolemia (Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Dedoussis GV et al. Eur J Clin Invest, 2004 Jun;34:402-9; Dedoussis GV et al. Hum Mutat, 2004 Mar;23:285-6; Humphries SE et al. J Mol Med (Berl), 2006 Mar;84:203-14; Taylor A et al. Clin Genet, 2007 Jun;71:561-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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:
This sequence change creates a premature translational stop signal (p.Gln384*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 19843101, 33740630). ClinVar contains an entry for this variant (Variation ID: 251688). For these reasons, this variant has been classified as Pathogenic.
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:
subject mutated among 2600 FH index cases screened = 1
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial hypercholesterolemia 1 (MIM#143890) and LDL cholesterol level QTL2 (MIM#143890). (I) 0108 - This gene is associated with both recessive and dominant disease. Biallelic individuals have an earlier and more severe onset (Gene Reviews). (I) 0112 - The condition associated with this gene has incomplete penetrance. Recent findings suggest that only 73% of individuals with a heterozygous LDLR pathogenic variant have elevated LDL levels (GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. Also known as p.(Gln363*) in the literature, this is a Cypriot founder mutation and co-segregates with p.(Asp386Glu) in families with familial hypercholesterolemia (PMID: 27578104). It was noted that in two families, this variant was found in isolation, without the missense variant (PMID: 25463123). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
The p.Q384* pathogenic mutation (also known as c.1150C>T), located in coding exon 8 of the LDLR gene, results from a C to T substitution at nucleotide position 1150. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This variant (also referred to as p.Q363*) been detected in individuals with features consistent with familial hypercholesterolemia (Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Dedoussis GV et al. Eur J Clin Invest, 2004 Jun;34:402-9; Dedoussis GV et al. Hum Mutat, 2004 Mar;23:285-6; Humphries SE et al. J Mol Med (Berl), 2006 Mar;84:203-14; Taylor A et al. Clin Genet, 2007 Jun;71:561-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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:
This sequence change creates a premature translational stop signal (p.Gln384*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 19843101, 33740630). ClinVar contains an entry for this variant (Variation ID: 251688). For these reasons, this variant has been classified as Pathogenic.
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 |
| Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene. | Jiang L | Atherosclerosis | 2017 | PMID: 28645073 |
| Genetic causes of monogenic familial hypercholesterolemia in the Greek population: Lessons, mistakes, and the way forward. | Mollaki V | Journal of clinical lipidology | 2016 | PMID: 27578104 |
| Familial Hypercholesterolemia in Greek children and their families: genotype-to-phenotype correlations and a reconsideration of LDLR mutation spectrum. | Mollaki V | Atherosclerosis | 2014 | PMID: 25463123 |
| Molecular spectrum of autosomal dominant hypercholesterolemia in France. | Marduel M | Human mutation | 2010 | PMID: 20809525 |
| Mutation screening in patients for familial hypercholesterolaemia (ADH). | Taylor A | Clinical genetics | 2010 | PMID: 19843101 |
| Multiplex ARMS analysis to detect 13 common mutations in familial hypercholesterolaemia. | Taylor A | Clinical genetics | 2007 | PMID: 17539906 |
| Mutational analysis in UK patients with a clinical diagnosis of familial hypercholesterolaemia: relationship with plasma lipid traits, heart disease risk and utility in relative tracing. | Humphries SE | Journal of molecular medicine (Berlin, Germany) | 2006 | PMID: 16389549 |
| FH clinical phenotype in Greek patients with LDL-R defective vs. negative mutations. | Dedoussis GV | European journal of clinical investigation | 2004 | PMID: 15200491 |
| 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 |
| Molecular characterization of familial hypercholesterolemia in German and Greek patients. | Dedoussis GV | Human mutation | 2004 | PMID: 14974088 |
| A double mutant LDL receptor allele in a cypriot family with heterozygous familial hypercholesterolemia. | Kotze MJ | Human genetics | 1997 | PMID: 9225977 |
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Text-mined citations for rs879254805 ...
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 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.