rs764797225
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000527.5(LDLR):c.303delG(p.Glu101AspfsTer105) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,386 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.303delG | p.Glu101AspfsTer105 | frameshift_variant | Exon 3 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251478Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135920
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461386Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726978
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:2
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Familial hypercholesterolemia Pathogenic:2
This sequence change creates a premature translational stop signal (p.Glu101Aspfs*105) 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). This variant is present in population databases (rs764797225, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with LDLR-related conditions. ClinVar contains an entry for this variant (Variation ID: 251126). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic variant based on current evidence: This variant deletes one nucleotide in exon 3 of the LDLR gene. This creates a frameshift and premature translational stop signal and is expected to result in an absent or non-functional protein product. Truncating variants in LDLR are known to be pathogenic (PMID: 20809525). This variant is rare in the general population and has been identified in 1/246260 chromosomes by the Genome Aggregation Database (gnomAD). This variant has been reported in individuals affected with familial hypercholesterolemia in UK (PMID: 17094996, 23680767). Based on available evidence, this variant is classified as Pathogenic. -
Homozygous familial hypercholesterolemia Pathogenic:1
The p.Glu101AspfsX105 variant in LDLR has been reported in 2 individuals with hypercholesterolemia (Sozen 2004, Tosi 2007). It has also been identified in 0.001% (1/113754) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID: 251126). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 101 and leads to a premature termination codon 105 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the LDLR gene is an established disease mechanism in autosomal dominant hypercholesterolemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hypercholesterolemia. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at