19-11111513-G-C
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.1061-1G>C variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000527.5 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1061-1G>C | splice_acceptor_variant | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1061-1G>C | splice_acceptor_variant | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 31
GnomAD4 exome Cov.: 31
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1AN XY: 74350
ClinVar
Submissions by phenotype
Familial hypercholesterolemia Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 27, 2023 | Variant summary: LDLR c.1061-1G>C 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. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Yu_1999). The variant was absent in 251190 control chromosomes. c.1061-1G>C has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Lind_2002, Yu_1999). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 12052488, 10487495, 18355452). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change affects an acceptor splice site in intron 7 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). 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: 10487495, 17539906, 28965616; Invitae). ClinVar contains an entry for this variant (Variation ID: 251637). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 10487495). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Oct 22, 2019 | The c.1061-1G>C variant in the LDLR gene disrupts the canonical splice acceptor site in intron 7 and is predicted to result in abnormal mRNA splicing. This variant has been reported in an individual with familial hypercholesterolemia (PMID: 10487495 ). It is absent from population databases such as gnomAD. Functional studies of this variant show a decrease in LDLR mRNA, skipping of exon 8 and alternative RNA editing using a cryptic acceptor splice site producing a frameshift mutation and a predicted premature stop codon (PMID: 10487495). In addition, another nucleotide change at the same position, c.1061-1G>A, has also been reported in individuals with familial hypercholesterolemia (PMID:17539906). The c.1061-1G>C variant in the LDLR gene is thus classified as likely pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 20, 2021 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 16, 2021 | This variant is located in a canonical splice-acceptor site and interferes with normal LDLR mRNA splicing. The variant has been reported in individuals with familial hypercholesterolemia in the published literature (PMID: 29407885 (2018) and 10487495 (1999)). In addition, a published study demonstrates that this variant aberrantly affects normal mRNA splicing (PMID: 10487495 (1999)). Based on the available information, this variant is classified as pathogenic. - |
Likely pathogenic, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Jan 29, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 29, 2023 | Published functional studies demonstrate two alternate splicing mechanisms, one which results in in-frame skipping of exon 8 and one which results in creation of a premature stop codon in exon 8 (Yu et al., 1999); Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); Different variants affecting the same splice site (c.1061-1 G>A, c.1061-1 G>T) have been reported in association with FH (HGMD); Also known as FH Honduras-1; This variant is associated with the following publications: (PMID: 10487495, 28965616, 29407885, 32906018, 34037665, 33955087, 17539906) - |
Hypercholesterolemia, familial, 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | curation;literature only | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Mar 01, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 31, 2022 | The c.1061-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 8 of the LDLR gene. This alteration has been reported in an individual with familial hypercholesterolemia. In addition, RNA and protein studies have revealed aberrant splicing that resulted in abolished expression of wild type LDLR protein (Yu L et al. Atherosclerosis. 1999;146:125-31). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. 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 pathogenic mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at