rs765696008

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_000527.5(LDLR):c.1187-10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,611,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

LDLR
NM_000527.5 intron

Scores

Splicing: ADA: 0.9998

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22

Conservation

PhyloP100: -0.371

Variant links:

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

LDLR links:

LDLR (HGNC:):

LDLR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-11113268-G-A is Pathogenic according to our data. Variant chr19-11113268-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 226349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113268-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.1187-10G>A		intron_variant		ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.1187-10G>A		intron_variant		1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151920

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000280

AC:

AN:

250138

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135578

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1459908

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726254

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000197

AC:

AN:

151920

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74170

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:22

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:13

Pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Jan 21, 2019	- -
Pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Jun 05, 2008	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	subjects mutated among 2600 FH index cases screened = 4 , family member = 2 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 11, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Each parent is heterozygous for the variant. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 26077743, 21865347) In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 1.00). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000226349). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2+PS3_Supporting+PS4_Moderate+PM3+PP4+PP1_Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Apr 24, 2023	This variant changes a single nucleotide in intron 8 of the LDLR gene and is predicted to create a new splice acceptor, eight nucleotides upstream from the canonical splice acceptor site. A RNA study with cells from a homozygous subject has confirmed that the usage of the new splice acceptor resulted in the mRNA that included the last eight nucleotides of intron 8 (PMID: 26077743). This creates a frameshift and premature translational stop signal and is expected to result in an absent or non-functional protein product. This variant has been identified in multiple Caucasian individuals diagnosed with familial hypercholesterolemia (PMID: 11668627, 12436241, 20145306, 21865347, 24075752). In a large Chinese family, this variant segregated with hypercholesterolemia in nine heterozygous individuals and one homozygous child who showed severe phenotype (PMID: 26077743). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 36325061). This variant has been identified in 7/250138 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic. -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 08, 2020	This variant has been reported in multiple individuals affected with familial hypercholesterolemia (FH), including one homozygous individual with severe phenotype (PMIDs: 11668627 (2001), 12436241 (2002), 16205024 (2005), 20145306 (2010), 24075752 (2013), and 26077743 (2015)). In addition, cell-based functional studies report this variant is damaging to LDLR protein activity by activating a cryptic splice acceptor site which leads to early termination of LDLR mRNA translation (PMIDs: 19208450 (2009), 21865347(2011), and 26077743 (2015)). Furthermore, this variant was shown to cosegregate with disease in a large family affected with familial hypercholesterolemia (FH) (PMID: 26077743 (2015)). Therefore, the variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2024	Identified in multiple unrelated individuals with FH in published literature (PMID: 12436241, 11668627, 16205024, 20145306, 24075752, 26077743, 30512145); Non-canonical splice site variant which cDNA sequencing demonstrated results inclusion of the last 8 nucleotides from intron 8 in transcripts from the variant allele, which is expected to lead to a a translational frameshift (PMID: 26077743, 19208450); Functional characterization in EBV-transformed lymphocytes showed a significant reduction in LDLR activity (PMID: 21865347, 19208450); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 32220565, 30512145, 12436241, 16205024, 20145306, 24075752, 33569482, 33740630, 34037665, 34456049, 33955087, 33994402, 26077743, 21865347, 19208450, 11668627) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 20, 2021	PVS1, PS3_moderate, PM3_supporting, PS4_moderate -
Pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 19, 2016	The patient had genetic testing for the familial hypercholesterolemia panel. The test included sequencing of three genes associated with familial hypercholesterolemia: LDLR, APOB and PCSK9. Results showed that the following variant was identified: c.1187-10G>A in the LDLR gene (NM_000527.4) The lab classifies this variant as pathogenic. Given the strong case data we consider this variant pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 13 unrelated cases of familial hypercholesterolemia (not including this patient's family), this is significant case data supporting the pathogenicity of this variant. Chmara et al., 2009, identified the c.1187-10G>A LDLR variant in 4 of 378 patients with familial hypercholesterolemia. They predicted this variant to be pathogenic and state that it resulted in deletion of consensus acceptor site and formation of a de novo acceptor site at 1187-8. Hooper et al., 2012, performed mutation testing of LDLR in 343 patients with possible, probable, or definite FH and found the c.1187-10G>A variant in 2 individuals in this cohort. Sun et al., 2015, identified a Chinese family with FH and found that the c.1187-10G>A variant segregated with disease in the family. It was also found in a homozygous state in one affected individual in the family with severe FH who had high cholesterol as well as tendon xanthomas. The c.1187-10G>A variant was not identified in 39 sporadic FH subjects or 288 healthy Chinese control subjects. They also gentoyped the cDNA of LDLR and found that the variant activated cryptic splice sites, resulting in a transcript that included the last eight nucleotides of intron 8 in the mRNA. Punzalan et al., 2005, performed genetic testing of LDLR for 60 unrelated Filipino patients with a clinical diagnosis of FH. They found the c.1187-10G>A mutation in 2 out of the 60 patients. Amsellem et al., 2002, performed genetic testing of 110 FH patients from an admixed population. They identified the c.1187-10G>A mutation in 2 patients in this cohort. Romano et al., 2011, identified the c.1187-10G>A variant in 2 individuals with FH. These patients had reduced LDLR residual activity on EBV-transformed B-lymphocytes as well as reduced LDLR residual activity on stimulated T-lymphocytes. Four web-based tools were used to determine whether the c.1187-10G>A variant affected the splice site. ASSP, HSF, and NetGene2 all identified a cryptic donor site generated by the c.1187-10G>A variant. All four software tools reported that the confidence scores of the cryptic donor site are higher than the natural splice site. The variant has not been seen in laboratory controls, published controls or individuals from publicly available population datasets. There is no variation at c.1187-10G>A listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 4/19/16). -

Familial hypercholesterolemia

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 28, 2017	Variant summary: The LDLR c.1187-10G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a disease-causing outcome for this variant. 5/5 splice prediction tools predict the creation of a cryptic splice site 8bp upstream of the canonical splice site at the exon-intron junction. A functional study that assayed splicing defects via cDNA analysis in a family affected by familial hypercholesterolemia showed that a heterozygous individual expresses both the WT allele as well as the variant allele (which includes the 8bp of retained intronic sequence), and a severely affected homozygous individual who expresses no detectable WT transcript (Sun_Sci Rep_2015). Additionally, another study analyzed residual LDLR activity in B- and T-lymphocytes in FH patients compared to control individuals and found that heterozygous patients have approximately half of LDLR activity of control individuals via flow cytometry experiments (Romano_JLR_2011), which supports the hypothesis that the variant is a null allele. This variant was found in the large control database ExAC at a frequency of 0.0000417 (5/119944 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). In addition, the observations of the variant in the ExAC dataset needs to be cautiously considered due to the cohort containing individuals that could harbor a LDLR phenotype. Furthermore, a publication, Sun_2015, shows the variant to cosegregate with disease in a large FH family, including the proband, who was homozygous for the variant and had a significantly elevated lipid level. Multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 09, 2023	This variant changes a single nucleotide in intron 8 of the LDLR gene and is predicted to create a new splice acceptor, eight nucleotides upstream from the canonical splice acceptor site. A RNA study with cells from a homozygous subject has confirmed that the usage of the new splice acceptor resulted in the mRNA that included the last eight nucleotides of intron 8 (PMID: 26077743). This creates a frameshift and premature translational stop signal and is expected to result in an absent or non-functional protein product. This variant has been identified in multiple Caucasian individuals diagnosed with familial hypercholesterolemia (PMID: 11668627, 12436241, 20145306, 21865347, 24075752). In a large Chinese family, this variant segregated with hypercholesterolemia in nine heterozygous individuals and one homozygous child who showed severe phenotype (PMID: 26077743). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 36325061). This variant has been identified in 7/250138 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	This sequence change falls in intron 8 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. This variant is present in population databases (rs765696008, gnomAD 0.006%). This variant has been observed in individuals with familial hypercholesterolemia (PMID: 11668627, 12436241, 20145306, 21865347, 24075752, 26077743). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 226349). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects LDLR function (PMID: 21865347). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Homozygous familial hypercholesterolemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 18, 2019

The c.1187-10G>A variant in LDLR has been reported in 10 heterozygous individuals and 1 homozygous individual with hypercholesterolemia and segregated with disease in 10 affected individuals from 2 families (Wang 2011, Amsellem 2002, Punzalan 2005, Chmara 2010, Sun 2015, Liang 2016). It has also been identified in 0.005% (1/18364) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID: 226349). This variant is located in the 3' splice region. Computational prediction tools and in vitro splicing assays are consistent with pathogenicity (Holla 2009). In vitro functional studies support an impact on protein function (Holla 2009, Romano 2011). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hypercholesterolemia. ACMG/AMP Criteria applied: PP1_Strong, PM3, PS3_Moderate, PS4_Moderate. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2023

The c.1187-10G>A intronic alteration consists of a G to A substitution 10 nucleotides before coding exon 9 of the LDLR gene. Based on data from gnomAD, the A allele has an overall frequency of 0.003% (7/250138) total alleles studied. This mutation has been described in individuals affected with familial hypercholesterolemia (FH) from different populations (Wang, 2001; Amsellem, 2002; Punzalan, 2005; Romano, 2011; Hooper, 2012; Sun, 2015). This nucleotide position is well conserved in available vertebrate species. LDLR protein showed reduced activity levels in patient derived lymphocytes in vitro (Romano, 2011). This variant was described to co-segregate with FH phenotype in a Chinese family and cDNA analysis revealed that this variant caused abnormal splicing (Sun, 2015). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

DANN

Benign

0.41

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AG_spliceai

1.0

Position offset: 2

DS_AL_spliceai

0.92

Position offset: 10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over