rs876657697
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000527.5(LDLR):c.1428dup(p.Asp477ArgfsTer59) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A475A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
LDLR
NM_000527.5 frameshift
NM_000527.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.80
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 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 19-11113599-G-GC is Pathogenic according to our data. Variant chr19-11113599-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 228357.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.1428dup | p.Asp477ArgfsTer59 | frameshift_variant | 10/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1428dup | p.Asp477ArgfsTer59 | frameshift_variant | 10/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Homozygous familial hypercholesterolemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 21, 2015 | The p.Asp477fs variant in LDLR has been reported in 2 German individuals with fa milial hypercholesterolemia (Weiss 2000, Bochmann 2001). It was absent from larg e population studies, though the ability of these studies to accurately detect i ndels may be limited. The p.Asp477fs variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 477 and le ads to a premature termination codon 59 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in individuals wi th familial hypercholesterolemia. In summary, the p.Asp477fs variant meets our c riteria to be classified as pathogenic for familial hypercholesterolemia in an a utosomal dominant manner based upon its predicted impact to the protein and abse nce from controls. - |
Hypercholesterolemia, familial, 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 06, 2022 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11196104, 23375686, 34037665, 11139254) - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 16, 2019 | The c.1428dupC pathogenic mutation, located in coding exon 10 of the LDLR gene, results from a duplication of C at nucleotide position 1428, causing a translational frameshift with a predicted alternate stop codon (p.D477Rfs*59). This alteration has been reported in association with familial hypercholesterolemia (FH) (Weiss N et al. J. Inherit. Metab. Dis., 2000 Dec;23:778-90; Bochmann H et al. Hum. Mutat., 2001;17:76-7; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Familial hypercholesterolemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 11, 2023 | This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 228357). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 11139254, 11196104, 23375686). This sequence change creates a premature translational stop signal (p.Asp477Argfs*59) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at