rs875989897
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePM2PP3_ModeratePP5_Very_Strong
The NM_000527.5(LDLR):c.313+2dup variant causes a splice donor change. The variant allele was found at a frequency of 0.00000274 in 1,460,880 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 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: 0.0000027 ( 0 hom. )
Consequence
LDLR
NM_000527.5 splice_donor
NM_000527.5 splice_donor
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.04
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 14 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.0472319 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.5, offset of -50, new splice context is: gagGTgcga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 19-11102787-G-GT is Pathogenic according to our data. Variant chr19-11102787-G-GT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 226317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.313+2dup | splice_donor_variant | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.313+2dup | splice_donor_variant | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 31
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251424Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135902
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460880Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726744
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GnomAD4 genome ? Cov.: 31
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:7
Pathogenic, no assertion criteria provided | clinical testing | Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital | Jul 04, 2013 | - - |
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 | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | Mar 01, 2016 | - - |
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
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 | subject mutated among 2600 FH index cases screened = 1, family member=1 - |
Likely pathogenic, criteria provided, single submitter | research | Iberoamerican FH Network | Mar 01, 2016 | - - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 21, 2018 | The c.313+2dupT intronic pathogenic mutation, results from a duplication of a T nucleotide two nucleotide positions after coding exon 3 of the LDLR gene. This alteration has been detected as homozgyous in multiple individuals with clinically confirmed homozygous familial hypercholesterolemia (HoFH) (Sánchez-Hernández RM et al. Circ Cardiovasc Genet, 2016 Dec;9:504-510; Alonso R et al. J Clin Lipidol Apr;10:953-961) and as heterozygous in multiple individuals with familial hypercholesterolemia (FH) (Bañares VG et al. J Clin Lipidol Feb;11:524-531; Gabová D et al. Physiol Res, 2017 Mar;66:75-84; Mozas P et al. Hum. Mutat., 2004 Aug;24:187). In one functional study, authors showed that this mutation impacts ligand binding and results in the skipping of in-frame exon 3 at the mRNA level (Etxebarria A et al. Hum. Mutat., 2012 Jan;33:232-43). In addition, a different alteration with the same molecular splicing impact, c.313+6T>C, has been detected in individuals with FH and has been shown at the mRNA level to induce exon 3 skipping (Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42). (Bourbon M et al. J. Med. Genet., 2009 May;46:352-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Familial hypercholesterolemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change falls in intron 3 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has been observed in individuals with familial hypercholesterolemia (PMID: 15241806, 21990180). ClinVar contains an entry for this variant (Variation ID: 226317). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 21990180). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at