chr19-11128005-C-A
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000527.5(LDLR):c.2312-3C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
LDLR
NM_000527.5 splice_region, intron
NM_000527.5 splice_region, intron
Scores
2
Splicing: ADA: 0.9919
2
Clinical Significance
Conservation
PhyloP100: 0.986
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]
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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 19-11128005-C-A is Pathogenic according to our data. Variant chr19-11128005-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 226391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11128005-C-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | c.2312-3C>A | splice_region_variant, intron_variant | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461694Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727156
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32
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GnomAD4 genome
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:11Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:7Uncertain:1
| Pathogenic, no assertion criteria provided | clinical testing | Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital | Jul 24, 2009 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 23, 2024 | This variant causes a C to A nucleotide substitution at the -3 position of intron 15 of the LDLR gene. Functional RNA studies have shown that this variant causes in-frame skipping of exon 16, resulting in the loss of the 26-amino acid transmembrane functional domain (PMID: 11317362). In vitro functional studies using EBV-transformed B-lymphocytes have shown that this variant causes a significant reduction in residual LDLR activity (PMID: 20045108, 21865347). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 11317362, 11668640, 12417285, 14624402, 16115486, 18718593, 25014035, 28353356, 28179607, 30710474, 32331935, 33740630). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 11317362, 11668640, 14624402, 16115486). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen | Oct 22, 2018 | The mutation leads to a change in the splice acceptor in intron 15 of the LDLR gene. It has already been described in the literature, detected in patients with familial hypercholesterolemia, and associated with elevated cholesterol and LDL-C levels. In in vitro models, the mutation leads to almost complete loss of LDL receptor activity. We observed this mutation in a patient with TC up to 520 mg/dl and LDL-C approx 420 mg/dl at the age of 45 years. PMID: 11317362, 21865347 - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II | May 24, 2021 | Reduced activity, in stimulated T-lymphocytes and EBV-transformed B-lymphocytes. - |
| Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
| Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
| Likely pathogenic, criteria provided, single submitter | research | Laboratory of Genetics and Molecular Cardiology, University of São Paulo | Mar 01, 2016 | - - |
| Uncertain significance, flagged submission | research | Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia | Jun 17, 2019 | - - |
Familial hypercholesterolemia Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 06, 2016 | Variant summary: The LDLR c.2312-3C>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant, and 5/5 splicing algorithms predict this variant to reduce the splice acceptor site strength. LDLR residual activity on stimulated T-lymphocytes from multiple heterozygous patients were approximately 50% of normal activity, suggesting that this variant results in little to no residual activity. This variant was not found in large and broad populations from ExAC. It has been reported as one of the common pathogenic variants that causes FH. Furthermore, 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 | Labcorp Genetics (formerly Invitae), Labcorp | Jul 20, 2023 | Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 226391). This variant has been observed in individuals with familial hypercholesterolemia (PMID: 11317362, 31491741). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 15 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. It affects a nucleotide within the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 22, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate skipping of exon 16 and reduced LDLR activity (PMID: 11317362, 21865347); Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); This variant is associated with the following publications: (PMID: 11317362, 21865347, 25525159, 18718593, 11668640, 30710474, 32331935, 32994617, 12628589, 12417285, 14624402, 16627557, 16115486, 28965616, 31345425, 31491741, 34040191, 33740630, 34756585, 34297352) - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 03, 2024 | The c.2312-3C>A intronic variant results from a C to A substitution 3 nucleotides upstream from coding exon 16 in the LDLR gene. This alteration has been detected in numerous individuals with familial hypercholesterolemia (FH) from a variety of ethnic backgrounds, and segregation with disease has been reported in multiple families (Liguori R et al. Hum. Mutat., 2001 May;17:433; García-García AB et al. Hum. Mutat., 2001 Nov;18:458-9; Pisciotta L et al. Atherosclerosis, 2005 Sep;182:153-9; Miyake Y et al. Atherosclerosis, 2009 Mar;203:153-60; Rubba P et al. Eur J Prev Cardiol, 2017 Jul;24:1051-1059). In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site. Functional studies have demonstrated skipping of exon 16, with the in-frame deletion of 26 amino acids, and reduced LDLR activity to approximately 50% of wild-type (Romano M et al. Atherosclerosis, 2010 Jun;210:493-6). This nucleotide position is highly conserved in available vertebrate species. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: 3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at