VCV000003744.35 - ClinVar

NM_000527.5(LDLR):c.2140+1G>A

Germline

Top reviewed classifications are shown here.

Submission summary:

19 submissions

19 submitters

5 conditions

Reviewed by expert panel

Pathogenic

Jun 2021 by ClinGen Famili… FDA Recognized Database

for Hypercholesterolemia, familial, 1

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000527.5(LDLR):c.2140+1G>A

Variation ID: 3744 Accession: VCV000003744.35

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.2 19: 11120523 (GRCh38) [ NCBI UCSC ] 19: 11231199 (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	May 21, 2016	Oct 8, 2024	Jun 18, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_000527.5:c.2140+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001195798.2:c.2140+1G>A		splice donor
NM_001195799.2:c.2017+1G>A		splice donor
NM_001195800.2:c.1636+1G>A		splice donor
NM_001195803.2:c.1606+290G>A		intron variant
NC_000019.10:g.11120523G>A
NC_000019.9:g.11231199G>A
NG_009060.1:g.36143G>A
LRG_274:g.36143G>A
LRG_274t1:c.2140+1G>A

... more HGVS ... less HGVS

Protein change

Other names

IVS14 ds G-A +1
IVS14, G-A, +1

Canonical SPDI

NC_000019.10:11120522:G:A

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.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA023643 LDLR-LOVD, British Heart Foundation: LDLR_000282 OMIM: 606945.0063 dbSNP: rs145787161 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	4076	4352

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	Pathogenic (13)	reviewed by expert panel	Jun 18, 2021	RCV000003942.33
Familial hypercholesterolemia	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Nov 22, 2023	RCV000775089.12
not provided	Pathogenic (1)	criteria provided, single submitter	Nov 23, 2021	RCV001787369.3
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	May 26, 2022	RCV002426486.2
LDLR-related disorder	Pathogenic (1)	no assertion criteria provided	Jul 23, 2024	RCV003398438.5

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.
Pathogenic (Jun 18, 2021)	reviewed by expert panel (ClinGen FH ACMG Specifications v1-1) Method: curation	Hypercholesterolemia, familial, 1 (Semidominant inheritance) Affected status: unknown Allele origin: germline	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel FDA Recognized Database Accession: SCV001960941.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/3baa34ee-ff35-4201-b317-1815827dce8e Comment: NM_000527.5(LDLR):c.2140+1G>A variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PP1_Strong, PM2, PS4_Moderate, PP4 and PS3_Supporting) as defined by the ClinGen … (more) NM_000527.5(LDLR):c.2140+1G>A variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PP1_Strong, PM2, PS4_Moderate, PP4 and PS3_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PVS1 - Variant is in canonical splice site and predicts a frameshift in exon 15. PP1_strong - Variant segregates with FH phenotype in 9 members of 4 families (9 informative meioses). PM2 - No population data was found for this allele in gnomAD (gnomAD v2.1.1). PS4_moderate - Variant meets PM2. Variant identified in 7 unrelated index cases fulfilling validated clinical criteria for FH from different labs. PP4 - Variant meets PM2. Variant found in 7 unrelated index cases fulfilling validated clinical criteria for FH. PS3_supporting - PMID:12522687 - Level 3 assay - study on htz patient's lymphocytes. An additional mRNA transcript of ~730 bp was detected; 214 bp retention of intron 14 causing a premature stop codon 99 amino acids later was the identified using cDNA sequencing. 46% LDLR particle clearance. (less)
Likely pathogenic (-)	criteria provided, single submitter (Wang et al. (Arterioscler Thromb Vasc Biol. 2016)) Method: clinical testing	Hypercholesterolemia, familial, 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Robarts Research Institute, Western University Accession: SCV000484793.1 First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016	Number of individuals with the variant: 1
Pathogenic (Dec 16, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV000503469.1 First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016	Comment: subject mutated among 2600 FH index cases screened = 1 Number of individuals with the variant: 1
Pathogenic (May 10, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hypercholesterolemia, familial, 1 Affected status: yes Allele origin: germline	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia Accession: SCV001432560.1 First in ClinVar: Sep 19, 2020 Last updated: Sep 19, 2020	Observation 1: Number of individuals with the variant: 1 Clinical Features: Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present) Observation 2: Number of individuals with the variant: 1 Clinical Features: Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present) Observation 3: Number of individuals with the variant: 1 Clinical Features: Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
Pathogenic (Nov 21, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002811548.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Sep 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003827739.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Aug 15, 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: SCV004825202.1 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 (9) PubMed: 11313767‚ 12522687‚ 15241806‚ 16199547‚ 20828696‚ 22883975‚ 23054246‚ 24627126‚ 27784735 Comment: The c.2140+1G>A intronic variant, also known as IVS14+1G>A, of the LDLR gene is located at the canonical donor splice site of intron 14. This variant … (more) The c.2140+1G>A intronic variant, also known as IVS14+1G>A, of the LDLR gene is located at the canonical donor splice site of intron 14. This variant has been reported in several (>7) individuals affected with Familial Hypercholesterolemia (FH) and segregated with disease in 14 members in a large pedigree (PMID: 12522687, 15241806, 20828696, 22883975, 23054246, 24627126, 27784735, 11313767). In-silico computational prediction tools suggest that the c.2140+1G>A variant likely leads to disturbed splicing (SpliceAI: 0.99), resulting in an aberrant or absence of protein product (PMID: 16199547). cDNA analysis using leukocyte derived mRNA revealed an insertion of a 214-bp intronic sequence between exons 14 and 15 due to activation of a cryptic splicing-donor site, resulting in the creation of a premature stop codon and production of a truncated protein that lacked transmembrane and cytoplasmic domains (PMID: 12522687). Experimental functional studies using heterozygous patient-derived peripheral lymphocytes have shown that this variant causes significant decrease in LDLR expression levels and LDL binding activity (PMID: 12522687). This variant is found to be absent in the general population database, gnomAD and interpreted as likely pathogenic/pathogenic by several ClinVar submitters including the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel (ClinVar ID: 3744). Therefore, the c.2140+1G>A intronic variant in LDLR gene is classified as 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: SCV000295891.2 First in ClinVar: Jul 29, 2016 Last updated: Oct 10, 2018	Publications: PubMed (3) PubMed: 12522687‚ 15241806‚ 20828696 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
Pathogenic (Mar 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial hypercholesterolemia (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge Accession: SCV000323001.1 First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016	Publications: PubMed (1) PubMed: 12522687 Comment: 0/200 non-FH alleles Observation 1: Observation 2: Comment on evidence: Heterozygous patients' lymphocytes, FACS assays Result: 50% LDLR activity
Pathogenic (Mar 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial hypercholesterolemia (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Fundacion Hipercolesterolemia Familiar Study: SAFEHEART Accession: SCV000607679.1 First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016	Publications: PubMed (1) PubMed: 12522687 Observation 1: Observation 2: Comment on evidence: Htz patients' lymphocytes, FACS assays Result: 50% LDLR activity
Likely pathogenic (Nov 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000914828.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (3) PubMed: 22883975‚ 20828696‚ 15241806 Comment: The LDLR c.2140+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.2140+1G>A … (more) The LDLR c.2140+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.2140+1G>A variant has been reported in at least three studies and is found in at least four probands with familial hypercholesterolemia in a heterozygous state (Mozas et al. 2004; Medeiros et al. 2010; Hooper et al. 2012). One of these patients also had a second splice site variant (Mozas et al. 2004). The c.2140+1G>A variant is reported at a frequency of 0.000116 in the European American population of the Exome Sequencing Project, but this is based on one allele in a region of good sequence coverage, so the variant is presumed to be rare. Due to the potential impact of splice donor variants, the c.2140+1G>A variant is classified as likely pathogenic for familial hypercholesterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (Nov 23, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002031164.2 First in ClinVar: Dec 12, 2021 Last updated: Mar 04, 2023	Comment: Not observed in large population cohorts (Lek et al., 2016); Canonical splice site variant predicted to result in abnormal gene splicing, which was confirmed by … (more) Not observed in large population cohorts (Lek et al., 2016); Canonical splice site variant predicted to result in abnormal gene splicing, which was confirmed by published PCR functional studies showing the insertion of 214 nucleotides into the intronic sequence resulting in a truncated protein product (Takada et al., 2002); Two other splice site variants affecting the same nucleotide (c.2140+1 G>T, c.2140+1 G>C) have been reported in the Human Gene Mutation Database in association with FH (Stenson et al., 2014); Reported in ClinVar (ClinVar Variant ID# 3744; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31345425, 24507775, 25525159, 12522687, 15241806, 20828696, 14673705, 22883975, 19837725, 32041611, 33303402, 34037665) (less)
Pathogenic (Jun 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000909193.2 First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024	Publications: PubMed (9) PubMed: 12522687‚ 15241806‚ 20828696‚ 22883975‚ 23054246‚ 24507775‚ 24627126‚ 27784735‚ 31345425 Comment: This intronic variant is predicted to abolish the canonical splice donor site of intron 14 in the LDLR gene. An experimental RNA study has shown … (more) This intronic variant is predicted to abolish the canonical splice donor site of intron 14 in the LDLR gene. An experimental RNA study has shown that this variant causes an insertion of a 214-base pair intronic sequence between exons 14 and 15 due to a cryptic splice donor activation, resulting in a frameshift and premature truncation (PMID: 12522687). An additional experimental functional study has shown that this variant causes a significant decrease in LDLR activity (PMID: 12522687). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 15241806, 20828696, 22883975, 23054246, 24507775, 24627126,27784735, 31345425; Color internal data), including over 90 individuals from a large pedigree where the variant has been shown to segregate with disease (PMID: 12522687). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in an individual affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 27784735). 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. Based on available evidence, this variant is classified as Pathogenic. (less)
Pathogenic (Nov 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: SCV000627027.9 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (5) PubMed: 28492532‚ 12522687‚ 15241806‚ 20828696‚ 23054246 Comment: This sequence change affects a donor splice site in intron 14 of the LDLR gene. RNA analysis indicates that disruption of this splice site induces … (more) This sequence change affects a donor splice site in intron 14 of the LDLR gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with familial hypercholesterolemia (PMID: 12522687, 15241806, 20828696, 23054246). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3744). Studies have shown that disruption of this splice site results in aberrant splicing and introduces a premature termination codon (PMID: 12522687). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (May 26, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002729253.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (7) PubMed: 10441197‚ 11313767‚ 12522687‚ 15241806‚ 20828696‚ 24507775‚ 32041611 Comment: The c.2140+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 14 of the LDLR gene. This canonical splice … (more) The c.2140+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 14 of the LDLR gene. This canonical splice site alteration has been reported in individuals with familial hypercholesterolemia (FH) and shown to segregate with the disease in a multi-generational family (Takada D et al. J. Hum. Genet., 2002;47:656-64; Mozas P et al. Hum. Mutat., 2004 Aug;24:187; Medeiros AM et al. Atherosclerosis, 2010 Oct;212:553-8). Moreover, this alteration has been shown to cause aberrant splicing that results in loss of the protein (Takada D et al. J. Hum. Genet., 2002;47:656-64). Additional alterations impacting the same donor site (c.2140+1G>T and c.2140+1G>C) have also been described in FH cases (Peeters AV et al. Mol Cell Probes, 1999 Aug;13:257-60; Heath KE et al. Eur J Hum Genet, 2001 Apr;9:244-52). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Oct 21, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	familial hypercholesterolemia Affected status: unknown Allele origin: unknown	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV005045743.1 First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024	Comment: The c.2140+1G>A intronic variant, also known as IVS14+1G>A, of the LDLR gene is located at the canonical donor splice site of intron 14. This variant … (more) The c.2140+1G>A intronic variant, also known as IVS14+1G>A, of the LDLR gene is located at the canonical donor splice site of intron 14. This variant has been reported in several (>7) individuals affected with Familial Hypercholesterolemia (FH) and segregated with disease in 14 members in a large pedigree (PMID: 12522687, 15241806, 20828696, 22883975, 23054246, 24627126, 27784735, 11313767). In-silico computational prediction tools suggest that the c.2140+1G>A variant likely leads to disturbed splicing (SpliceAI: 0.99), resulting in an aberrant or absence of protein product (PMID: 16199547). cDNA analysis using leukocyte derived mRNA revealed an insertion of a 214-bp intronic sequence between exons 14 and 15 due to activation of a cryptic splicing-donor site, resulting in the creation of a premature stop codon and production of a truncated protein that lacked transmembrane and cytoplasmic domains (PMID: 12522687). Experimental functional studies using heterozygous patient-derived peripheral lymphocytes have shown that this variant causes significant decrease in LDLR expression levels and LDL binding activity (PMID: 12522687). This variant is found to be absent in the general population database, gnomAD and interpreted as likely pathogenic/pathogenic by several ClinVar submitters including the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel (ClinVar ID: 3744). Therefore, the c.2140+1G>A intronic variant in LDLR gene is classified as pathogenic. (less)
Pathogenic (Jan 01, 2004)	no assertion criteria provided Method: literature only	HYPERCHOLESTEROLEMIA, FAMILIAL, 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024107.7 First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024	Publications: PubMed (3) PubMed: 12522687‚ 12910492‚ 14673705 Comment on evidence: Takada et al. (2002) described a novel splice site mutation in the LDLR gene, IVS14+1G-A, which genealogic research confirmed was shared by 14 of 1,135 … (more) Takada et al. (2002) described a novel splice site mutation in the LDLR gene, IVS14+1G-A, which genealogic research confirmed was shared by 14 of 1,135 members of an American Caucasian pedigree descended from a common ancestor and affected with familial hypercholesterolemia (FHCL1; 143890). The mutation resulted in an abruptly truncated LDLR protein, reducing functional LDLR activity by half in heterozygous carriers of the mutant allele. Takada et al. (2002) stated this was the largest familial hypercholesterolemia kindred described, and of 208 members screened for this LDLR mutation, 94 carriers and 114 noncarriers were identified. Strikingly lower total cholesterol and LDL cholesterol values were observed among most of the LDLR mutation carriers who were simultaneously homozygous for the -265C allele of the -265C-T polymorphism of the APOA2 gene (107670.0002). In vitro transfection assays showed that transcriptional activity of the APOA2 promoter was reduced by 30% in the -265C allele as compared with the -265T allele. The variant of the APOA2 gene was associated with reduced plasma LDL cholesterol only in familial hypercholesterolemia patients. In the same large family reported by Takada et al. (2002), Takada et al. (2003) found that a SNP in the growth hormone receptor gene (GHR), resulting in a L526I (600946.0028) substitution, influenced plasma levels of high density lipoprotein (HDL) cholesterol in affected family members with the LDLR mutation. The lowest levels of plasma HDL were observed among leu/leu homozygotes, highest levels among ile/ile homozygotes, and intermediate levels among leu/ile heterozygotes. No such effect was observed among noncarriers of the LDLR mutation. In the pedigree reported by Takada et al. (2002), Sato et al. (2004) demonstrated a significant modification of the phenotype of familial hypercholesterolemia resulting from the IVS14+1G-A mutation by the arg287 variation in the EPHX2 gene (132811.0001). (less)
Pathogenic (Jul 23, 2024)	no assertion criteria provided Method: clinical testing	LDLR-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004105956.2 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The LDLR c.2140+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant is also referred to as IVS14+1G>A … (more) The LDLR c.2140+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant is also referred to as IVS14+1G>A in the literature. This variant has been reported in many individuals with familial hypercholesterolemia and segregated with disease in a large family (see, for example, Takada et al 2002. PubMed ID: 12522687; eTable1, Sturm et al 2021. PubMed ID: 34037665, Supplementary Table 6, Marco-Benedí. 2021. PubMed ID: 34456049). RT-PCR studies suggest this variant impacts mRNA splicing (Takada et al 2002. PubMed ID: 12522687). This variant has not been reported in a large population database, indicating this variant is rare. Variants that disrupt the consensus splice donor site in LDLR are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (Jun 10, 2008)	no assertion criteria provided Method: clinical testing	Familial hypercholesterolemia Affected status: yes Allele origin: germline	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital Accession: SCV000268658.1 First in ClinVar: May 21, 2016 Last updated: May 21, 2016	Number of individuals with the variant: 1
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Comment:

NM_000527.5(LDLR):c.2140+1G>A variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PP1_Strong, PM2, PS4_Moderate, PP4 and PS3_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PVS1 - Variant is in canonical splice site and predicts a frameshift in exon 15. PP1_strong - Variant segregates with FH phenotype in 9 members of 4 families (9 informative meioses). PM2 - No population data was found for this allele in gnomAD (gnomAD v2.1.1). PS4_moderate - Variant meets PM2. Variant identified in 7 unrelated index cases fulfilling validated clinical criteria for FH from different labs. PP4 - Variant meets PM2. Variant found in 7 unrelated index cases fulfilling validated clinical criteria for FH. PS3_supporting - PMID:12522687 - Level 3 assay - study on htz patient's lymphocytes. An additional mRNA transcript of ~730 bp was detected; 214 bp retention of intron 14 causing a premature stop codon 99 amino acids later was the identified using cDNA sequencing. 46% LDLR particle clearance.

Comment:

The c.2140+1G>A intronic variant, also known as IVS14+1G>A, of the LDLR gene is located at the canonical donor splice site of intron 14. This variant has been reported in several (>7) individuals affected with Familial Hypercholesterolemia (FH) and segregated with disease in 14 members in a large pedigree (PMID: 12522687, 15241806, 20828696, 22883975, 23054246, 24627126, 27784735, 11313767). In-silico computational prediction tools suggest that the c.2140+1G>A variant likely leads to disturbed splicing (SpliceAI: 0.99), resulting in an aberrant or absence of protein product (PMID: 16199547). cDNA analysis using leukocyte derived mRNA revealed an insertion of a 214-bp intronic sequence between exons 14 and 15 due to activation of a cryptic splicing-donor site, resulting in the creation of a premature stop codon and production of a truncated protein that lacked transmembrane and cytoplasmic domains (PMID: 12522687). Experimental functional studies using heterozygous patient-derived peripheral lymphocytes have shown that this variant causes significant decrease in LDLR expression levels and LDL binding activity (PMID: 12522687). This variant is found to be absent in the general population database, gnomAD and interpreted as likely pathogenic/pathogenic by several ClinVar submitters including the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel (ClinVar ID: 3744). Therefore, the c.2140+1G>A intronic variant in LDLR gene is classified as pathogenic.

Comment:

The LDLR c.2140+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.2140+1G>A variant has been reported in at least three studies and is found in at least four probands with familial hypercholesterolemia in a heterozygous state (Mozas et al. 2004; Medeiros et al. 2010; Hooper et al. 2012). One of these patients also had a second splice site variant (Mozas et al. 2004). The c.2140+1G>A variant is reported at a frequency of 0.000116 in the European American population of the Exome Sequencing Project, but this is based on one allele in a region of good sequence coverage, so the variant is presumed to be rare. Due to the potential impact of splice donor variants, the c.2140+1G>A variant is classified as likely pathogenic for familial hypercholesterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

Not observed in large population cohorts (Lek et al., 2016); Canonical splice site variant predicted to result in abnormal gene splicing, which was confirmed by published PCR functional studies showing the insertion of 214 nucleotides into the intronic sequence resulting in a truncated protein product (Takada et al., 2002); Two other splice site variants affecting the same nucleotide (c.2140+1 G>T, c.2140+1 G>C) have been reported in the Human Gene Mutation Database in association with FH (Stenson et al., 2014); Reported in ClinVar (ClinVar Variant ID# 3744; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31345425, 24507775, 25525159, 12522687, 15241806, 20828696, 14673705, 22883975, 19837725, 32041611, 33303402, 34037665)

Comment:

This intronic variant is predicted to abolish the canonical splice donor site of intron 14 in the LDLR gene. An experimental RNA study has shown that this variant causes an insertion of a 214-base pair intronic sequence between exons 14 and 15 due to a cryptic splice donor activation, resulting in a frameshift and premature truncation (PMID: 12522687). An additional experimental functional study has shown that this variant causes a significant decrease in LDLR activity (PMID: 12522687). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 15241806, 20828696, 22883975, 23054246, 24507775, 24627126,27784735, 31345425; Color internal data), including over 90 individuals from a large pedigree where the variant has been shown to segregate with disease (PMID: 12522687). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in an individual affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 27784735). 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. Based on available evidence, this variant is classified as Pathogenic.

Comment:

This sequence change affects a donor splice site in intron 14 of the LDLR gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with familial hypercholesterolemia (PMID: 12522687, 15241806, 20828696, 23054246). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3744). Studies have shown that disruption of this splice site results in aberrant splicing and introduces a premature termination codon (PMID: 12522687). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.2140+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 14 of the LDLR gene. This canonical splice site alteration has been reported in individuals with familial hypercholesterolemia (FH) and shown to segregate with the disease in a multi-generational family (Takada D et al. J. Hum. Genet., 2002;47:656-64; Mozas P et al. Hum. Mutat., 2004 Aug;24:187; Medeiros AM et al. Atherosclerosis, 2010 Oct;212:553-8). Moreover, this alteration has been shown to cause aberrant splicing that results in loss of the protein (Takada D et al. J. Hum. Genet., 2002;47:656-64). Additional alterations impacting the same donor site (c.2140+1G>T and c.2140+1G>C) have also been described in FH cases (Peeters AV et al. Mol Cell Probes, 1999 Aug;13:257-60; Heath KE et al. Eur J Hum Genet, 2001 Apr;9:244-52). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Comment:

The LDLR c.2140+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant is also referred to as IVS14+1G>A in the literature. This variant has been reported in many individuals with familial hypercholesterolemia and segregated with disease in a large family (see, for example, Takada et al 2002. PubMed ID: 12522687; eTable1, Sturm et al 2021. PubMed ID: 34037665, Supplementary Table 6, Marco-Benedí. 2021. PubMed ID: 34456049). RT-PCR studies suggest this variant impacts mRNA splicing (Takada et al 2002. PubMed ID: 12522687). This variant has not been reported in a large population database, indicating this variant is rare. Variants that disrupt the consensus splice donor site in LDLR are expected to be pathogenic. This variant is interpreted 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Six years' experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias.	Dron JS	BMC medical genomics	2020	PMID: 32041611
Risk of Premature Atherosclerotic Disease in Patients With Monogenic Versus Polygenic Familial Hypercholesterolemia.	Trinder M	Journal of the American College of Cardiology	2019	PMID: 31345425
Homozygous Familial Hypercholesterolemia in Spain: Prevalence and Phenotype-Genotype Relationship.	Sánchez-Hernández RM	Circulation. Cardiovascular genetics	2016	PMID: 27784735
Cardiovascular risk assessment of dyslipidemic children: analysis of biomarkers to identify monogenic dyslipidemia.	Medeiros AM	Journal of lipid research	2014	PMID: 24627126
Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol.	Lange LA	American journal of human genetics	2014	PMID: 24507775
Use of targeted exome sequencing as a diagnostic tool for Familial Hypercholesterolaemia.	Futema M	Journal of medical genetics	2012	PMID: 23054246
Genetic analysis of familial hypercholesterolaemia in Western Australia.	Hooper AJ	Atherosclerosis	2012	PMID: 22883975
Update of the Portuguese Familial Hypercholesterolaemia Study.	Medeiros AM	Atherosclerosis	2010	PMID: 20828696
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR.	Mozas P	Human mutation	2004	PMID: 15241806
Soluble epoxide hydrolase variant (Glu287Arg) modifies plasma total cholesterol and triglyceride phenotype in familial hypercholesterolemia: intrafamilial association study in an eight-generation hyperlipidemic kindred.	Sato K	Journal of human genetics	2004	PMID: 14673705
Growth hormone receptor variant (L526I) modifies plasma HDL cholesterol phenotype in familial hypercholesterolemia: intra-familial association study in an eight-generation hyperlipidemic kindred.	Takada D	American journal of medical genetics. Part A	2003	PMID: 12910492
Interaction between the LDL-receptor gene bearing a novel mutation and a variant in the apolipoprotein A-II promoter: molecular study in a 1135-member familial hypercholesterolemia kindred.	Takada D	Journal of human genetics	2002	PMID: 12522687
A molecular genetic service for diagnosing individuals with familial hypercholesterolaemia (FH) in the United Kingdom.	Heath KE	European journal of human genetics : EJHG	2001	PMID: 11313767
Intronic mutations at splice junctions in the low-density lipoprotein receptor gene.	Peeters AV	Molecular and cellular probes	1999	PMID: 10441197
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/3baa34ee-ff35-4201-b317-1815827dce8e	-	-	-	-
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Record last updated Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_000527.5(LDLR):c.2140+1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs145787161 ...