rs879254687
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_000527.5(LDLR):c.818-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Genomes: not found (cov: 32)
Consequence
LDLR
NM_000527.5 splice_acceptor
NM_000527.5 splice_acceptor
Scores
3
2
2
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 7.35
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 16 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.0472319 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 19-11107390-A-G is Pathogenic according to our data. Variant chr19-11107390-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 251471.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-11107390-A-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.818-2A>G | splice_acceptor_variant | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.818-2A>G | splice_acceptor_variant | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:4
Pathogenic, criteria provided, single submitter | research | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Mar 01, 2016 | 0/190 non-FH alleles - |
Pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Pathogenic, criteria provided, single submitter | research | Laboratory of Genetics and Molecular Cardiology, University of São Paulo | Mar 01, 2016 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Dec 13, 2021 | The NM_000527.5(LDLR):c.818-2A>G variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PP1_Moderate, PM2, PP4, PS3_Supporting and PS4_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 +2 AG splice site and has been proven to result in retention of 10 nt of intron5, which lead to out of frame consequence: p.Val273Glufs*31, so PVS1 is met. PP1_moderate - variant segregates with FH phenotype in 5 informative meiosis from 2 families from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge - 3 relatives with the phenotype have the variant and 2 relatives without phenotype do not have the variant. PP1_Moderate is met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PP4 - variant meets PM2. Identified in 3 unrelated index cases who fulfill SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge. PP4 is met PS3_supporting - Level 3 FS: Medeiros et al., 2010 (PMID 20828696) - Htz patients' lymphocytes, RNA assays - results: Retention of 10 nt of intron5 (p.Val273Glufs*31) --- an aberrant transcript was identified, so PS3_Supporting is met PS4_supporting - variant meets PM2. Identified in 3 unrelated index cases who fulfill SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge. PS4_Supporting is met. - |
Familial hypercholesterolemia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 21, 2023 | Variant summary: LDLR c.818-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. At least one publication reports experimental evidence that this variant affects mRNA splicing, leading to the retention of 10 nucleotides of intron 5 (Medeiros_2010). The variant was absent in 251436 control chromosomes (gnomAD). c.818-2A>G has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia and has been shown to segregate with disease in affected families (Bourbon_2008, Jiang_2016, Kim_2022). These data indicate that the variant is very likely to be associated with disease. Six ClinVar submitters including an expert panel (ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 25, 2022 | For these reasons, this variant has been classified as Pathogenic. 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: 251471). Disruption of this splice site has been observed in individual(s) with familial hypercholesterolemia (PMID: 17765246). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 5 of the LDLR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). - |
LDLR-related condition Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 09, 2022 | The LDLR c.818-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in individuals with Hypercholesterolemia (Bourbon et al. 2009. PubMed ID: 19411563; Medeiros et al. 2010. PubMed ID: 20828696) and interpreted as pathogenic by ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/251471/). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice acceptor site in LDLR are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 10, 2022 | The c.818-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 6 in the LDLR gene. This alteration has been identified in two index patients in a familial hypercholesterolemia (FH) cohort and was reported to segregate with disease (Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-4). This mutation was also detected in the compound heterozygous state with another pathogenic LDLR mutation in a patient with a clinical diagnosis of homozygous FH (Jiang L et al. J Clin Lipidol Dec;10:538-546.e5). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). A disease-causing mutation impacting the same canonical acceptor splice site, c.818-1G>A, has also been described (Humphries SE et al. J. Mol. Med., 2006 Mar;84:203-14). RNA studies for both c.818-1G>A and c.818-2A>G have been reported to cause retention of the same 10 intronic nucleotides between exons 5 and 6, resulting in a frameshift with a predicted alternate stop codon (Xie L et al. Chin. Med. J., 2007 Oct;120:1694-9; Medeiros AM et al. Atherosclerosis, 2010 Oct;212:553-8). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D;D
GERP RS
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_AG_spliceai
Position offset: 16
DS_AL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at