rs879255159
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000527.5(LDLR):c.2187_2197delAAAGGTCAGCT(p.Lys730HisfsTer48) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000527.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.2187_2197delAAAGGTCAGCT | p.Lys730HisfsTer48 | frameshift_variant | Exon 15 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461828Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727204
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:2
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Cardiovascular phenotype Pathogenic:1
The c.2187_2197del11 pathogenic mutation, located in coding exon 15 of the LDLR gene, results from a deletion of 11 nucleotides at nucleotide positions 2187 to 2197, causing a translational frameshift with a predicted alternate stop codon (p.K730Hfs*48). This variant has been detected in familial hypercholesterolemia cohorts (Marduel M et al. Hum Mutat, 2010 Nov;31:E1811-24; Futema M et al. Atherosclerosis, 2013 Jul;229:161-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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
For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). This particular variant has been reported in the literature in two families affected with hypercholesterolemia (PMID: 20809525, 23669246). This variant is also known in the literature as p.Leu729Leufs*39. This sequence change deletes 11 nucleotides from exon 15 of the LDLR mRNA (c.2187_2197del), causing a frameshift at codon 730. This creates a premature translational stop signal (p.Lys730Hisfs*48) and is expected to result in an absent or disrupted protein product. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at