VCV000162499.37 - ClinVar

NM_000527.5(LDLR):c.1359-1G>A

Germline

Top reviewed classifications are shown here.

Submission summary:

26 submissions

26 submitters

7 conditions

Reviewed by expert panel

Pathogenic

Aug 2022 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.1359-1G>A

Variation ID: 162499 Accession: VCV000162499.37

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.2 19: 11113534 (GRCh38) [ NCBI UCSC ] 19: 11224210 (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	Jan 18, 2015	Nov 24, 2024	Aug 28, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000527.5:c.1359-1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_001195798.2:c.1359-1G>A		splice acceptor
NM_001195799.2:c.1236-1G>A		splice acceptor
NM_001195800.2:c.855-1G>A		splice acceptor
NM_001195803.2:c.978-1G>A		splice acceptor
NR_106946.1:n.61G>A		non-coding transcript variant
NC_000019.10:g.11113534G>A
NC_000019.9:g.11224210G>A
NG_009060.1:g.29154G>A
LRG_274:g.29154G>A
LRG_274t1:c.1359-1G>A

... more HGVS ... less HGVS

Protein change

Other names

IVS9 as G-A -1

Canonical SPDI

NC_000019.10:11113533: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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA023463 LDLR-LOVD, British Heart Foundation: LDLR_001405 dbSNP: rs139617694 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
MIR6886	-	-	-	GRCh38	-	53

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.
Homozygous familial hypercholesterolemia	Pathogenic (1)	criteria provided, single submitter	Dec 23, 2015	RCV000844728.12
Hypercholesterolemia, familial, 1	Pathogenic (15)	reviewed by expert panel	Aug 28, 2022	RCV000172962.34
Familial hypercholesterolemia	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 24, 2023	RCV000775066.18
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jul 29, 2024	RCV001579677.14
Hypercholesterolemia	Pathogenic (1)	criteria provided, single submitter	Jun 1, 2014	RCV002051685.12
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Jun 10, 2022	RCV002381462.9
See cases	Pathogenic (1)	criteria provided, single submitter	Dec 8, 2021	RCV004584357.1

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.
Pathogenic (Aug 28, 2022)	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2) Method: curation	Hypercholesterolemia, familial, 1 (Semidominant inheritance) Affected status: unknown Allele origin: germline	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel FDA Recognized Database Accession: SCV002568030.1 First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7df0b854-4c43-4327-b5a3-3421ff6c6a46 Comment: The NM_000527.5(LDLR):c.1359-1G>A variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1, PP1_Strong, PS4, PM2, PP4 and PS3_Supporting as defined by the … (more) The NM_000527.5(LDLR):c.1359-1G>A variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1, PP1_Strong, PS4, PM2, PP4 and PS3_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PVS1 - variant is in canonical - 1 splice site and causes a frameshift in exon 10 (p.Thr454Leufs51, from Holla et al., 2009 (PMID 19208450)), so PVS1 is met. PP1_strong - variant segregates with FH phenotype in 9 informative meiosis from at least 5 families: - 5 informative meiosis from 4 families from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière): 5 relatives with the variant have LDL-C >75th percentile. - 4 informative meiosis from at least 1 family from Mayo lab (Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory), Ambry lab (Ambry Genetics) and Arca lab (Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca), but are confirmed to be the same: 2 relatives with the variant had LDL >75th percentile and 2 relatives negative for variant had LDL <50th percentile. --- so PP1_Strong is met. PS4 - variant meets PM2 and was identified in: - 25 unrelated index cases (22 cases with DLCN >=6, 3 with possible Simon Broome FH from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France; - 2 unrelated index cases (MFH101: DLCN of 8, MFH116: meets MEDPED definite) reported by Mayo lab (Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory), Ambry lab (Ambry Genetics) and Arca lab (Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca), but are confirmed to be the same; - 1 index case with Dutch lipid clinic network >=6 from Robarts Research Institute, Canada; - 1 index case with DLCN >= 6 from Color Health, Inc., USA. --- 29 cases (no additional bibliographic search was done because number of index cases is already over 10), so PS4 is met. PM2 - PopMax MAF = 0.00002940 (0.003%) in European non-Finnish genomes (gnomAD v3.1.2). It is below 0.02%, so PM2 is met. PP4 - variant meets PM2 and was identified in at least 29 unrelated index cases (see PS4 for details), so PP4 is met. PS3_supporting - Level 2/3 FS: Holla et al., 2009 (PMID 19208450): Htz patients' Epstein Barr virus transformed lymphocytes, RNA assays - results: skipping of the first 7 nts from exon 10 in 23% of mRNAs (p.Thr454Leufs51) --- aberrant transcript is confirmed by sequencing and is quantified, but it is not above 25% of total transcript, so PS3_Supporting is met. (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: SCV000484787.1 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: SCV000503342.1 First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016	Comment: subjects mutated among 2600 FH index cases screened = 11 , family members = 2 with co-segregation / previously described in association with FH Number of individuals with the variant: 11
Pathogenic (Mar 30, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Hypercholesterolemia Affected status: yes Allele origin: germline	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille Accession: SCV000583825.1 First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017 Comment: ACMG Guidelines: Pathogenic (i)	Number of individuals with the variant: 20 Clinical Features: Hyperbetalipoproteinemia (present) , Hypercholesterolemia (present) Indication for testing: Familial Hypercholesterolemia Sex: mixed Geographic origin: France Comment on evidence: Dutch Lipid Clinic Scoring : Definite FH Secondary finding: no
Pathogenic (Dec 23, 2015)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Homozygous familial hypercholesterolemia (Autosomal dominant inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000271383.3 First in ClinVar: May 29, 2016 Last updated: Aug 31, 2019	Publications: PubMed (10) PubMed: 10441197‚ 25525159‚ 25637381‚ 11668640‚ 7616128‚ 10735632‚ 10090473‚ 22390909‚ 19208450‚ 26036859 Comment: The c.1359-1G>A variant in LDLR has been reported in >80 individuals with famili al hypercholesterolemia (FH), segregated with disease in 8 affected relatives fr om … (more) The c.1359-1G>A variant in LDLR has been reported in >80 individuals with famili al hypercholesterolemia (FH), segregated with disease in 8 affected relatives fr om 3 families (Peeters 1995, Lombarid 1995 and 2000, Garcia-Garcia 2001, Braenne 2015), and has been identified in 1/8600 European American chromosomes by the N HLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs139617 694). This variant occurs in the invariant region (+/- 1,2) of the splice consen sus sequence and is predicted to cause altered splicing leading to an abnormal o r absent protein. Heterozygous loss of LDLR function is an established disease m echanism in familial hypercholesterolemia. In summary, this variant meets our cr iteria to be classified as pathogenic for familial hypercholesterolemia in an au tosomal dominant manner. ACMG/AMP criteria applied: PVS1, PP1_S, PS4, PM2 (Richa rds 2015). (less) Number of individuals with the variant: 2
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	Hypercholesterolemia, familial, 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics, University Hospital of Duesseldorf Accession: SCV004046792.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023
Pathogenic (Nov 24, 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: SCV000544700.9 First in ClinVar: Apr 16, 2017 Last updated: Feb 20, 2024	Publications: PubMed (11) PubMed: 28492532‚ 9254862‚ 10735632‚ 11668640‚ 11857755‚ 15241806‚ 21382890‚ 21475731‚ 22390909‚ 25154303‚ 10090473 Comment: This sequence change affects an acceptor splice site in intron 9 of the LDLR gene. RNA analysis indicates that disruption of this splice site induces … (more) This sequence change affects an acceptor splice site in intron 9 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 individuals with familial hypercholesterolemia (PMID: 9254862, 10735632, 11668640, 11857755, 15241806, 21382890, 21475731, 22390909, 25154303). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162499). Studies have shown that disruption of this splice site results in activation of a cryptic acceptor splice site and introduces a premature termination codon (PMID: 10090473). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Dec 08, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	see cases Affected status: yes Allele origin: unknown	Institute of Human Genetics, University Hospital Muenster Accession: SCV002577889.2 First in ClinVar: Oct 08, 2022 Last updated: Jul 07, 2024	Comment: ACMG categories: PVS1,PM2,PP4 Number of individuals with the variant: 1 Clinical Features: Hypercholesterolemia (present) Age: 30-39 years Sex: female Tissue: blood
Likely pathogenic (-)	criteria provided, single submitter (Submitter's publication) Method: research	Familial Hypercholesterolemia (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute for Integrative and Experimental Genomics, University of Luebeck Accession: SCV000212138.1 First in ClinVar: Jun 20, 2015 Last updated: Jun 20, 2015	Publications: PubMed (1) PubMed: 26036859
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: SCV000295393.2 First in ClinVar: Jul 29, 2016 Last updated: Oct 10, 2018	Publications: PubMed (7) PubMed: 11668640‚ 11857755‚ 12436241‚ 7616128‚ 9254862‚ 15199436‚ 25154303 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 Observation 5: Number of individuals with the variant: 1 Observation 6: Number of individuals with the variant: 1 Observation 7: 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: unknown Allele origin: germline	Fundacion Hipercolesterolemia Familiar Study: SAFEHEART Accession: SCV000607593.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017	Publications: PubMed (1) PubMed: 19208450 Observation 1: Observation 2: Comment on evidence: Htz patients' Epstein Barr virus transformed lymphocytes, RNA assays Result: skipping of the first 7 nts from exon 10 in 23% of mRs (p.Thr454Leufs*51)
Pathogenic (Dec 07, 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: SCV002798849.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (May 18, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003925909.1 First in ClinVar: May 27, 2023 Last updated: May 27, 2023	Comment: Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; … (more) Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; One of the most common pathogenic variants associated with FH in the Netherlands (Lombardi et al., 2000; Holla et al., 2009; Kusters et al., 2011; van der Graaf et al., 2011; Kindt et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); Functional studies suggest activation of a cryptic splice site resulting in a frameshift and premature stop codon (Rodningen et al., 1999; Holla et al., 2009); This variant is associated with the following publications: (PMID: 25637381, 21310417, 21382890, 21475731, 15199436, 22390909, 25525159, 9254862, 24507775, 11668640, 11857755, 12436241, 15241806, 15556094, 23936638, 31447099, 26036859, 33303402, 32041611, 33740630, 34037665, 34040191, 33955087, 35379577, 35913489, 10090473, 19208450, 7616128, 10735632, 9925649, 25154303) (less)
Pathogenic (Jul 18, 2023)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV004219946.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (47) PubMed: 24507775‚ 25637381‚ 31447099‚ 32041611‚ 33303402‚ 33740630‚ 34037665‚ 34040191‚ 26036859‚ 21475731‚ 21382890‚ 19208450‚ 15241806‚ 15199436‚ 10735632‚ 10441197‚ 20506408‚ 23936638‚ 27765764‚ 30415195‚ 27824480‚ 12124988‚ 25887683‚ 15556092‚ 24916650‚ 16627557‚ 21310417‚ 33508743‚ 15523646‚ 21868016‚ 16792510‚ 21957200‚ 11600564‚ 26802169‚ 30293936‚ 31653860‚ 24503134‚ 35137788‚ 32989269‚ 22390909‚ 25154303‚ 10090473‚ 9254862‚ 7616128‚ 11668640‚ 11857755‚ 12436241 Comment: The LDLR c.1359-1G>A variant disrupts a canonical splice-acceptor site and interferes with normal LDLR mRNA splicing. This variant has been reported in the published literature … (more) The LDLR c.1359-1G>A variant disrupts a canonical splice-acceptor site and interferes with normal LDLR mRNA splicing. This variant has been reported in the published literature in individuals affected with hypercholesterolemia (PMIDs: 11857755 (2002), 11668640 (2001), 10735632 (2000), 7616128 (1995)). The variant has been reported to segregate with hypercholesterolemia in an affected family (PMID: 9254862 (1997). A functional study indicates that this variant impacts protein function (PMID: 19208450 (2009)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (May 10, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003825400.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
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: SCV000909167.2 First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024	Publications: PubMed (13) PubMed: 7616128‚ 9254862‚ 10090473‚ 10735632‚ 11668640‚ 11857755‚ 12436241‚ 15241806‚ 21382890‚ 21475731‚ 25154303‚ 33955087‚ 34037665 Comment: This variant causes a G to A nucleotide substitution at the -1 position of intron 9 of the LDLR gene. Splice site prediction tools suggest … (more) This variant causes a G to A nucleotide substitution at the -1 position of intron 9 of the LDLR gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. A quantitative RNA study has shown that this variant causes a deletion of the first seven nucleotides of exon 10 due to a cryptic splice acceptor activation, and is expected to cause a frameshift and premature truncation (PMID: 10090473). This variant has been reported in hundreds of individuals affected with familial hypercholesterolemia (PMID: 7616128, 9254862, 10090473, 10735632, 11668640, 11857755, 12436241, 15241806, 21382890, 21475731, 25154303, 33955087, 34037665). It has been shown that this variant segregates with disease in multiple affected individuals in two families (PMID: 9254862, 25154303). 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)
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: SCV004829745.1 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 (13) PubMed: 7616128‚ 9254862‚ 10090473‚ 10735632‚ 11668640‚ 11857755‚ 12436241‚ 15241806‚ 21382890‚ 21475731‚ 25154303‚ 33955087‚ 34037665 Comment: This variant causes a G to A nucleotide substitution at the -1 position of intron 9 of the LDLR gene. Splice site prediction tools suggest … (more) This variant causes a G to A nucleotide substitution at the -1 position of intron 9 of the LDLR gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. A quantitative RNA study has shown that this variant causes a deletion of the first seven nucleotides of exon 10 due to a cryptic splice acceptor activation, and is expected to cause a frameshift and premature truncation (PMID: 10090473). This variant has been reported in hundreds of individuals affected with familial hypercholesterolemia (PMID: 7616128, 9254862, 10090473, 10735632, 11668640, 11857755, 12436241, 15241806, 21382890, 21475731, 25154303, 33955087, 34037665). It has been shown that this variant segregates with disease in multiple affected individuals in two families (PMID: 9254862, 25154303). 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) Number of individuals with the variant: 3
Pathogenic (Jun 10, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002690264.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (5) PubMed: 10090473‚ 21475731‚ 25154303‚ 26036859‚ 9254862 Comment: The c.1359-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 10 of the LDLR gene. This alteration … (more) The c.1359-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 10 of the LDLR gene. This alteration has been previously reported in unrelated individuals, as well as co-segregating in families, with hypercholesterolemia and has been reported as originating in the Netherlands (Peeters AV et al. Hum Genet. 1997;100(2):266-70; Kusters DM et al. Neth Heart J. 2011;19(4):175-182; Brænne I et al. BMC Cardiovasc Disord. 2014;14:108; Brænne I et al. Eur. J. Hum. Genet., 2016 Feb;24:191-7). One functional study suggested this alteration results in a partial loss of mRNA, while another study reported this alteration as causing aberrant splicing in which the first 7 base pairs of exon 10 were deleted, predicting an early stop codon (Peeters AV et al. Hum Genet. 1997;100(2):266-70; Rødningen OK et al. Hum Mutat. 1999;13(3):186-96). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. (less)
Pathogenic (Jul 29, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005413314.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (12) PubMed: 19208450‚ 22390909‚ 24507775‚ 25154303‚ 32041611‚ 33740630‚ 33955087‚ 34037665‚ 34040191‚ 35379577‚ 7616128‚ 9254862 Comment: PP1_strong, PP4, PM2, PS3_supporting, PS4, PVS1_strong Number of individuals with the variant: 1
Pathogenic (Jun 01, 2014)	no assertion criteria provided Method: research	Hypercholesterolaemia (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	CSER _CC_NCGL, University of Washington Study: ESP 6500 variant annotation Accession: SCV000190289.1 First in ClinVar: Jan 18, 2015 Last updated: Jan 18, 2015 Comment: Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
Pathogenic (Mar 17, 2014)	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: SCV000268613.1 First in ClinVar: May 21, 2016 Last updated: May 21, 2016	Number of individuals with the variant: 1
Pathogenic (-)	no assertion criteria provided Method: research	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum Accession: SCV000606409.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000733821.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001808113.1 First in ClinVar: Aug 26, 2021 Last updated: Aug 26, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001918435.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Pathogenic (Nov 24, 2023)	no assertion criteria provided Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: yes Allele origin: germline	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas Accession: SCV004171581.1 First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023
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Comment:

The NM_000527.5(LDLR):c.1359-1G>A variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1, PP1_Strong, PS4, PM2, PP4 and PS3_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PVS1 - variant is in canonical - 1 splice site and causes a frameshift in exon 10 (p.Thr454Leufs*51, from Holla et al., 2009 (PMID 19208450)), so PVS1 is met. PP1_strong - variant segregates with FH phenotype in 9 informative meiosis from at least 5 families: - 5 informative meiosis from 4 families from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière): 5 relatives with the variant have LDL-C >75th percentile. - 4 informative meiosis from at least 1 family from Mayo lab (Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory), Ambry lab (Ambry Genetics) and Arca lab (Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca), but are confirmed to be the same: 2 relatives with the variant had LDL >75th percentile and 2 relatives negative for variant had LDL <50th percentile. --- so PP1_Strong is met. PS4 - variant meets PM2 and was identified in: - 25 unrelated index cases (22 cases with DLCN >=6, 3 with possible Simon Broome FH from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France; - 2 unrelated index cases (MFH101: DLCN of 8, MFH116: meets MEDPED definite) reported by Mayo lab (Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory), Ambry lab (Ambry Genetics) and Arca lab (Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca), but are confirmed to be the same; - 1 index case with Dutch lipid clinic network >=6 from Robarts Research Institute, Canada; - 1 index case with DLCN >= 6 from Color Health, Inc., USA. --- 29 cases (no additional bibliographic search was done because number of index cases is already over 10), so PS4 is met. PM2 - PopMax MAF = 0.00002940 (0.003%) in European non-Finnish genomes (gnomAD v3.1.2). It is below 0.02%, so PM2 is met. PP4 - variant meets PM2 and was identified in at least 29 unrelated index cases (see PS4 for details), so PP4 is met. PS3_supporting - Level 2/3 FS: Holla et al., 2009 (PMID 19208450): Htz patients' Epstein Barr virus transformed lymphocytes, RNA assays - results: skipping of the first 7 nts from exon 10 in 23% of mRNAs (p.Thr454Leufs*51) --- aberrant transcript is confirmed by sequencing and is quantified, but it is not above 25% of total transcript, so PS3_Supporting is met.

Comment:

The c.1359-1G>A variant in LDLR has been reported in >80 individuals with famili al hypercholesterolemia (FH), segregated with disease in 8 affected relatives fr om 3 families (Peeters 1995, Lombarid 1995 and 2000, Garcia-Garcia 2001, Braenne 2015), and has been identified in 1/8600 European American chromosomes by the N HLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs139617 694). This variant occurs in the invariant region (+/- 1,2) of the splice consen sus sequence and is predicted to cause altered splicing leading to an abnormal o r absent protein. Heterozygous loss of LDLR function is an established disease m echanism in familial hypercholesterolemia. In summary, this variant meets our cr iteria to be classified as pathogenic for familial hypercholesterolemia in an au tosomal dominant manner. ACMG/AMP criteria applied: PVS1, PP1_S, PS4, PM2 (Richa rds 2015).

Comment:

This sequence change affects an acceptor splice site in intron 9 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 individuals with familial hypercholesterolemia (PMID: 9254862, 10735632, 11668640, 11857755, 15241806, 21382890, 21475731, 22390909, 25154303). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162499). Studies have shown that disruption of this splice site results in activation of a cryptic acceptor splice site and introduces a premature termination codon (PMID: 10090473). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

Comment:

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; One of the most common pathogenic variants associated with FH in the Netherlands (Lombardi et al., 2000; Holla et al., 2009; Kusters et al., 2011; van der Graaf et al., 2011; Kindt et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); Functional studies suggest activation of a cryptic splice site resulting in a frameshift and premature stop codon (Rodningen et al., 1999; Holla et al., 2009); This variant is associated with the following publications: (PMID: 25637381, 21310417, 21382890, 21475731, 15199436, 22390909, 25525159, 9254862, 24507775, 11668640, 11857755, 12436241, 15241806, 15556094, 23936638, 31447099, 26036859, 33303402, 32041611, 33740630, 34037665, 34040191, 33955087, 35379577, 35913489, 10090473, 19208450, 7616128, 10735632, 9925649, 25154303)

Comment:

The LDLR c.1359-1G>A variant disrupts a canonical splice-acceptor site and interferes with normal LDLR mRNA splicing. This variant has been reported in the published literature in individuals affected with hypercholesterolemia (PMIDs: 11857755 (2002), 11668640 (2001), 10735632 (2000), 7616128 (1995)). The variant has been reported to segregate with hypercholesterolemia in an affected family (PMID: 9254862 (1997). A functional study indicates that this variant impacts protein function (PMID: 19208450 (2009)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.

Comment:

This variant causes a G to A nucleotide substitution at the -1 position of intron 9 of the LDLR gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. A quantitative RNA study has shown that this variant causes a deletion of the first seven nucleotides of exon 10 due to a cryptic splice acceptor activation, and is expected to cause a frameshift and premature truncation (PMID: 10090473). This variant has been reported in hundreds of individuals affected with familial hypercholesterolemia (PMID: 7616128, 9254862, 10090473, 10735632, 11668640, 11857755, 12436241, 15241806, 21382890, 21475731, 25154303, 33955087, 34037665). It has been shown that this variant segregates with disease in multiple affected individuals in two families (PMID: 9254862, 25154303). 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:

The c.1359-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 10 of the LDLR gene. This alteration has been previously reported in unrelated individuals, as well as co-segregating in families, with hypercholesterolemia and has been reported as originating in the Netherlands (Peeters AV et al. Hum Genet. 1997;100(2):266-70; Kusters DM et al. Neth Heart J. 2011;19(4):175-182; Brænne I et al. BMC Cardiovasc Disord. 2014;14:108; Brænne I et al. Eur. J. Hum. Genet., 2016 Feb;24:191-7). One functional study suggested this alteration results in a partial loss of mRNA, while another study reported this alteration as causing aberrant splicing in which the first 7 base pairs of exon 10 were deleted, predicting an early stop codon (Peeters AV et al. Hum Genet. 1997;100(2):266-70; Rødningen OK et al. Hum Mutat. 1999;13(3):186-96). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Phenotypic and genotypic characterization of familial hypercholesterolemia in French adult and pediatric populations.	Fourgeaud M	Journal of clinical lipidology	2022	PMID: 35379577
Screening for Familial Hypercholesterolemia in Small Towns: Experience from 11 Brazilian Towns in the Hipercolbrasil Program.	Jannes CE	Arquivos brasileiros de cardiologia	2022	PMID: 35137788
A randomized controlled trial of genetic testing and cascade screening in familial hypercholesterolemia.	Ajufo E	Genetics in medicine : official journal of the American College of Medical Genetics	2021	PMID: 34040191
Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis.	Sturm AC	JAMA cardiology	2021	PMID: 34037665
Founder effects facilitate the use of a genotyping-based approach to molecular diagnosis in Swedish patients with familial hypercholesterolaemia.	Benedek P	Journal of internal medicine	2021	PMID: 33955087
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
Comparison of the mutation spectrum and association with pre and post treatment lipid measures of children with heterozygous familial hypercholesterolaemia (FH) from eight European countries.	Futema M	Atherosclerosis	2021	PMID: 33508743
Combined hyperlipidemia is genetically similar to isolated hypertriglyceridemia.	Gill PK	Journal of clinical lipidology	2021	PMID: 33303402
Identifying rare, medically relevant variation via population-based genomic screening in Alabama: opportunities and pitfalls.	Bowling KM	Genetics in medicine : official journal of the American College of Medical Genetics	2021	PMID: 32989269
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
Quantifying the polygenic contribution to variable expressivity in eleven rare genetic disorders.	Oetjens MT	Nature communications	2019	PMID: 31653860
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network.	eMERGE Consortium. Electronic address: [email protected]	American journal of human genetics	2019	PMID: 31447099
Spectrum of mutations of familial hypercholesterolemia in the 22 Arab countries.	Alhababi D	Atherosclerosis	2018	PMID: 30415195
Autosomal dominant hypercholesterolemia in Catalonia: Correspondence between clinical-biochemical and genetic diagnostics in 967 patients studied in a multicenter clinical setting.	Martín-Campos JM	Journal of clinical lipidology	2018	PMID: 30293936
The molecular genetic background of familial hypercholesterolemia: data from the Slovak nation-wide survey.	Gabčová D	Physiological research	2017	PMID: 27824480
Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically.	Wang J	Arteriosclerosis, thrombosis, and vascular biology	2016	PMID: 27765764
Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France.	Wintjens R	Journal of lipid research	2016	PMID: 26802169
Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction.	Brænne I	European journal of human genetics : EJHG	2016	PMID: 26036859
Improving the cost-effectiveness equation of cascade testing for familial hypercholesterolaemia.	Pears R	Current opinion in lipidology	2015	PMID: 25887683
Actionable exomic incidental findings in 6503 participants: challenges of variant classification.	Amendola LM	Genome research	2015	PMID: 25637381
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.	Xiong HY	Science (New York, N.Y.)	2015	PMID: 25525159
Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach.	Versmissen J	European journal of human genetics : EJHG	2015	PMID: 24916650
Whole-exome sequencing in an extended family with myocardial infarction unmasks familial hypercholesterolemia.	Brænne I	BMC cardiovascular disorders	2014	PMID: 25154303
Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol.	Lange LA	American journal of human genetics	2014	PMID: 24507775
LipidSeq: a next-generation clinical resequencing panel for monogenic dyslipidemias.	Johansen CT	Journal of lipid research	2014	PMID: 24503134
Quality assessment of the genetic test for familial hypercholesterolemia in the Netherlands.	Kindt I	Cholesterol	2013	PMID: 23936638
Cardiovascular risk in relation to functionality of sequence variants in the gene coding for the low-density lipoprotein receptor: a study among 29,365 individuals tested for 64 specific low-density lipoprotein-receptor sequence variants.	Huijgen R	European heart journal	2012	PMID: 22390909
LDL-apheresis depletes apoE-HDL and pre-β1-HDL in familial hypercholesterolemia: relevance to atheroprotection.	Orsoni A	Journal of lipid research	2011	PMID: 21957200
Reduced penetrance of autosomal dominant hypercholesterolemia in a high percentage of families: importance of genetic testing in the entire family.	Garcia-Garcia AB	Atherosclerosis	2011	PMID: 21868016
Founder mutations in the Netherlands: geographical distribution of the most prevalent mutations in the low-density lipoprotein receptor and apolipoprotein B genes.	Kusters DM	Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation	2011	PMID: 21475731
Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children.	van der Graaf A	Circulation	2011	PMID: 21382890
An APEX-based genotyping microarray for the screening of 168 mutations associated with familial hypercholesterolemia.	Dušková L	Atherosclerosis	2011	PMID: 21310417
Functionality of sequence variants in the genes coding for the low-density lipoprotein receptor and apolipoprotein B in individuals with inherited hypercholesterolemia.	Huijgen R	Human mutation	2010	PMID: 20506408
Effects of intronic mutations in the LDLR gene on pre-mRNA splicing: Comparison of wet-lab and bioinformatics analyses.	Holla ØL	Molecular genetics and metabolism	2009	PMID: 19208450
Molecular genetic testing for familial hypercholesterolemia in the Netherlands: a stepwise screening strategy enhances the mutation detection rate.	Lombardi MP	Genetic testing	2006	PMID: 16792510
Analysis of sequence variations in the LDL receptor gene in Spain: general gene screening or search for specific alterations?	Blesa S	Clinical chemistry	2006	PMID: 16627557
Large heterogeneity of mutations in the gene encoding the low-density lipoprotein receptor in subjects with familial hypercholesterolaemia.	Muller PY	Atherosclerosis. Supplements	2004	PMID: 15556092
LDL-receptor mutations in Europe.	Dedoussis GV	Human mutation	2004	PMID: 15523646
Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR.	Mozas P	Human mutation	2004	PMID: 15241806
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
Intronic mutations outside of Alu-repeat-rich domains of the LDL receptor gene are a cause of familial hypercholesterolemia.	Amsellem S	Human genetics	2002	PMID: 12436241
The UMD-LDLR database: additions to the software and 490 new entries to the database.	Villéger L	Human mutation	2002	PMID: 12124988
Comparison of SSCP and DHPLC for the detection of LDLR mutations in a New Zealand cohort.	Bunn CF	Human mutation	2002	PMID: 11857755
Molecular genetics of familial hypercholesterolemia in Spain: Ten novel LDLR mutations and population analysis.	García-García AB	Human mutation	2001	PMID: 11668640
Genetic diagnosis of familial hypercholesterolemia in a South European outbreed population: influence of low-density lipoprotein (LDL) receptor gene mutations on treatment response to simvastatin in total, LDL, and high-density lipoprotein cholesterol.	Chaves FJ	The Journal of clinical endocrinology and metabolism	2001	PMID: 11600564
Molecular genetic testing for familial hypercholesterolemia: spectrum of LDL receptor gene mutations in The Netherlands.	Lombardi MP	Clinical genetics	2000	PMID: 10735632
Intronic mutations at splice junctions in the low-density lipoprotein receptor gene.	Peeters AV	Molecular and cellular probes	1999	PMID: 10441197
Mutant transcripts of the LDL receptor gene: mRNA structure and quantity.	Rødningen OK	Human mutation	1999	PMID: 10090473
Mutational and genetic origin of LDL receptor gene mutations detected in both Belgian and Dutch familial hypercholesterolemics.	Peeters AV	Human genetics	1997	PMID: 9254862
Mutations in the low density lipoprotein receptor gene of familial hypercholesterolemic patients detected by denaturing gradient gel electrophoresis and direct sequencing.	Lombardi P	Journal of lipid research	1995	PMID: 7616128
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7df0b854-4c43-4327-b5a3-3421ff6c6a46	-	-	-	-
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Text-mined citations for rs139617694 ...

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

NM_000527.5(LDLR):c.1359-1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs139617694 ...