This variant changes 1 nucleotide in exon 9 of the EGF precursor homology domain of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15241806, 16250003, 18096825). It has also been reported in an individual suspected to be affected with familial hypercholesterolemia (PMID: 34037665). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1200C>A (p.Tyr400Ter)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic
5 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
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NM_000527.5(LDLR):c.1200C>A (p.Tyr400Ter)
Variation ID: 251728 Accession: VCV000251728.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11113291 (GRCh38) [ NCBI UCSC ] 19: 11223967 (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 Sep 30, 2017 Feb 25, 2025 Nov 15, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.1200C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Tyr400Ter nonsense NM_001195798.2:c.1200C>A NP_001182727.1:p.Tyr400Ter nonsense NM_001195799.2:c.1077C>A NP_001182728.1:p.Tyr359Ter nonsense NM_001195800.2:c.696C>A NP_001182729.1:p.Tyr232Ter nonsense NM_001195803.2:c.819C>A NP_001182732.1:p.Tyr273Ter nonsense NC_000019.10:g.11113291C>A NC_000019.9:g.11223967C>A NG_009060.1:g.28911C>A LRG_274:g.28911C>A LRG_274t1:c.1200C>A LRG_274p1:p.Tyr400Ter - Protein change
- Y400*, Y273*, Y232*, Y359*
- Other names
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- Canonical SPDI
- NC_000019.10:11113290:C: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 |
4222 | 4523 | |
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 (3) |
criteria provided, multiple submitters, no conflicts
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Mar 25, 2016 | RCV000237899.2 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 18, 2023 | RCV000775059.10 | |
| Pathogenic (1) |
criteria provided, single submitter
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Nov 15, 2024 | RCV004992122.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Pathogenic
(Mar 25, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: literature only
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
LDLR-LOVD, British Heart Foundation
Accession: SCV000295292.2
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
|
|
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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
|
Fundacion Hipercolesterolemia Familiar
Study: SAFEHEART
Accession: SCV000607573.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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Pathogenic
(Nov 16, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000909160.2
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This variant changes 1 nucleotide in exon 9 of the EGF precursor homology domain of the LDLR gene, creating a premature translation stop signal. This … (more)
This variant changes 1 nucleotide in exon 9 of the EGF precursor homology domain of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15241806, 16250003, 18096825). It has also been reported in an individual suspected to be affected with familial hypercholesterolemia (PMID: 34037665). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
|
|
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Pathogenic
(Sep 18, 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: SCV000941734.5
First in ClinVar: Aug 14, 2019 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: 251728). 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: 251728). This variant is also known as p.Y379X. This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 15241806, 16250003, 18096825; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr400*) 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
(Nov 15, 2024)
C
Contributing to aggregate classification
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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: SCV005609289.1
First in ClinVar: Jan 13, 2025 Last updated: Jan 13, 2025 |
Comment:
The p.Y400* pathogenic mutation (also known as c.1200C>A), located in coding exon 9 of the LDLR gene, results from a C to A substitution at … (more)
The p.Y400* pathogenic mutation (also known as c.1200C>A), located in coding exon 9 of the LDLR gene, results from a C to A substitution at nucleotide position 1200. This changes the amino acid from a tyrosine to a stop codon within coding exon 9. This variant (also referred to as p.Y379X) was reported in multiple individuals with features consistent with familial hypercholesterolemia (Mozas P et al. Hum Mutat, 2004 Aug;24:187; Fouchier SW et al. Hum Mutat, 2005 Dec;26:550-6; Marco-Benedí V et al. Atherosclerosis, 2022 May;349:211-218). 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
(-)
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
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Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Accession: SCV000606355.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 251728). This variant is also known as p.Y379X. This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 15241806, 16250003, 18096825; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr400*) 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).
Comment:
The p.Y400* pathogenic mutation (also known as c.1200C>A), located in coding exon 9 of the LDLR gene, results from a C to A substitution at nucleotide position 1200. This changes the amino acid from a tyrosine to a stop codon within coding exon 9. This variant (also referred to as p.Y379X) was reported in multiple individuals with features consistent with familial hypercholesterolemia (Mozas P et al. Hum Mutat, 2004 Aug;24:187; Fouchier SW et al. Hum Mutat, 2005 Dec;26:550-6; Marco-Benedí V et al. Atherosclerosis, 2022 May;349:211-218). 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.
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:
This variant changes 1 nucleotide in exon 9 of the EGF precursor homology domain of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15241806, 16250003, 18096825). It has also been reported in an individual suspected to be affected with familial hypercholesterolemia (PMID: 34037665). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 251728). This variant is also known as p.Y379X. This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 15241806, 16250003, 18096825; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr400*) 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).
Comment:
The p.Y400* pathogenic mutation (also known as c.1200C>A), located in coding exon 9 of the LDLR gene, results from a C to A substitution at nucleotide position 1200. This changes the amino acid from a tyrosine to a stop codon within coding exon 9. This variant (also referred to as p.Y379X) was reported in multiple individuals with features consistent with familial hypercholesterolemia (Mozas P et al. Hum Mutat, 2004 Aug;24:187; Fouchier SW et al. Hum Mutat, 2005 Dec;26:550-6; Marco-Benedí V et al. Atherosclerosis, 2022 May;349:211-218). 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Lipoprotein(a) in hereditary hypercholesterolemia: Influence of the genetic cause, defective gene and type of mutation. | Marco-Benedí V | Atherosclerosis | 2022 | PMID: 34456049 |
| Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis. | Sturm AC | JAMA cardiology | 2021 | PMID: 34037665 |
| Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene. | Jiang L | Atherosclerosis | 2017 | PMID: 28645073 |
| Molecular spectrum of autosomal dominant hypercholesterolemia in France. | Marduel M | Human mutation | 2010 | PMID: 20809525 |
| Femoral atherosclerosis in heterozygous familial hypercholesterolemia: influence of the genetic defect. | Junyent M | Arteriosclerosis, thrombosis, and vascular biology | 2008 | PMID: 18096825 |
| Update of the molecular basis of familial hypercholesterolemia in The Netherlands. | Fouchier SW | Human mutation | 2005 | PMID: 16250003 |
| Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR. | Mozas P | Human mutation | 2004 | PMID: 15241806 |
Text-mined citations for rs879254827 ...
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.