VCV000003745.8 - ClinVar

NC_000019.10:g.11089411del

Germline

Classification

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.

(5)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(3); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NC_000019.10:g.11089411del

Variation ID: 3745 Accession: VCV000003745.8

Type and length

Deletion, 1 bp

Location

Cytogenetic: 19p13.2 19: 11089411 (GRCh38) [ NCBI UCSC ] 19: 11200087 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Apr 4, 2013	Apr 20, 2024	Dec 18, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000527.4:c.-138delT
NM_001195798.1:c.-138delT
NM_001195799.1:c.-138delT
NM_001195800.1:c.-138delT
NM_001195803.1:c.-138delT
NR_163945.1:n.249del		non-coding transcript variant
NC_000019.10:g.11089411del
NC_000019.9:g.11200087del
NG_009060.1:g.5031del
LRG_274:g.5031del
LRG_274t1:c.-138del

... more HGVS ... less HGVS

Protein change

Other names

FH Pyrgos
-45T DEL

Canonical SPDI

NC_000019.10:11089410:T:

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA023477 LDLR-LOVD, British Heart Foundation: LDLR_000959 OMIM: 606945.0064 dbSNP: rs387906307 VarSome

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
Gene	OMIM	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	4085	4361
LDLR-AS1	-	-	-	GRCh38	-	204

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.
Hypercholesterolemia, familial, 1	Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 18, 2023	RCV000003943.20
Familial hypercholesterolemia	Uncertain significance (1)	criteria provided, single submitter	Feb 22, 2023	RCV002512730.10

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.
Uncertain significance (Feb 22, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003472875.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 14616764‚ 17625505 Comment: This variant occurs in a non-coding region of the LDLR gene. It does not change the encoded amino acid sequence of the LDLR protein. This … (more) This variant occurs in a non-coding region of the LDLR gene. It does not change the encoded amino acid sequence of the LDLR protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 14616764). It has also been observed to segregate with disease in related individuals. This variant is also known as c.-45del. ClinVar contains an entry for this variant (Variation ID: 3745). Studies have shown that this variant alters LDLR gene expression (PMID: 14616764, 17625505). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Likely Pathogenic (Dec 18, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 (Semidominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004840284.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (3) PubMed: 14616764‚ 17625505‚ 35631530 Comment: This variant deletes one nucleotide at the -138 position in the conserved SP1 binding site in the promoter region of the LDLR gene. This variant … (more) This variant deletes one nucleotide at the -138 position in the conserved SP1 binding site in the promoter region of the LDLR gene. This variant is also known as c.-45del and FH-Pyrgos in the literature. Functional studies using lymphocytes derived from a heterozygous individual have shown that this variant resulted in reduced LDLR activity and absent mRNA transcription (PMID: 14616764). An in-vitro functional study using transfected mammalian cells has shown that this variant causes a significant reduction in promoter activity (PMID: 14616764, 17625505). This variant has been reported in at least two unrelated individuals affected with familial hypercholesterolemia (PMID: 14616764, 35631530). It has been shown that this variant segregates with disease in three affected individuals in one family (PMID: 14616764). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less) Number of individuals with the variant: 1
Likely pathogenic (Mar 25, 2016)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: literature only	Familial hypercholesterolemia (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	LDLR-LOVD, British Heart Foundation Accession: SCV000294388.2 First in ClinVar: Jul 29, 2016 Last updated: May 30, 2018	Publications: PubMed (1) PubMed: 14616764 Number of individuals with the variant: 1
Likely pathogenic (Mar 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation, literature only	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: SCV000599300.1 First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017	Publications: PubMed (1) PubMed: 14616764 Observation 1: Observation 2: Comment on evidence: Assay Description:Heterologous cells (HepG2), luciferase assays; RNA from whole blood assay Result: 5% reporter gene expression; no mutant mRNA detected
Pathogenic (Nov 01, 2003)	no assertion criteria provided Method: literature only	FH PYRGOS Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024108.2 First in ClinVar: Apr 04, 2013 Last updated: Jun 23, 2019	Publications: PubMed (1) PubMed: 14616764 Comment on evidence: In a patient with familial hypercholesterolemia (FHCL1; 143890), Dedoussis et al. (2003) identified a novel mutation in repeat 3 of the LDLR gene promoter, -45delT. … (more) In a patient with familial hypercholesterolemia (FHCL1; 143890), Dedoussis et al. (2003) identified a novel mutation in repeat 3 of the LDLR gene promoter, -45delT. Analysis of a neutral polymorphism in LDLR mRNA from the patient's white blood cells showed that the expression of 1 allele was significantly reduced, and cells had only 24% of LDLR activity by binding and uptake of iodine-labeled LDL. Transient transfection studies using a luciferase gene reporter revealed that the -45delT mutation considerably reduced the transcriptional activity of the LDLR promoter and strongly suggested that the mutation was the cause of the familial hypercholesterolemia phenotype. The proband was a female in her late thirties; her father was reported to have elevated cholesterol levels and had undergone bypass surgery at the age of 70. (less)

Comment:

This variant occurs in a non-coding region of the LDLR gene. It does not change the encoded amino acid sequence of the LDLR protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 14616764). It has also been observed to segregate with disease in related individuals. This variant is also known as c.-45del. ClinVar contains an entry for this variant (Variation ID: 3745). Studies have shown that this variant alters LDLR gene expression (PMID: 14616764, 17625505). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

This variant deletes one nucleotide at the -138 position in the conserved SP1 binding site in the promoter region of the LDLR gene. This variant is also known as c.-45del and FH-Pyrgos in the literature. Functional studies using lymphocytes derived from a heterozygous individual have shown that this variant resulted in reduced LDLR activity and absent mRNA transcription (PMID: 14616764). An in-vitro functional study using transfected mammalian cells has shown that this variant causes a significant reduction in promoter activity (PMID: 14616764, 17625505). This variant has been reported in at least two unrelated individuals affected with familial hypercholesterolemia (PMID: 14616764, 35631530). It has been shown that this variant segregates with disease in three affected individuals in one family (PMID: 14616764). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic Variant ABCC1 rs45511401 Is Associated with Increased Response to Statins in Patients with Familial Hypercholesterolemia.	Dagli-Hernandez C	Pharmaceutics	2022	PMID: 35631530
A functional mutation in the LDLR promoter (-139C>G) in a patient with familial hypercholesterolemia.	Smith AJ	European journal of human genetics : EJHG	2007	PMID: 17625505
FH-Pyrgos: a novel mutation in the promoter (-45delT) of the low-density lipoprotein receptor gene associated with familial hypercholesterolemia.	Dedoussis GV	Clinical genetics	2003	PMID: 14616764

Text-mined citations for rs387906307 ...

These 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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NC_000019.10:g.11089411del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs387906307 ...