rs387906304
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000527.5(LDLR):c.925_931del(p.Pro309LysfsTer59) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000932 in 1,608,706 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E308E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000527.5 frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.925_931del | p.Pro309LysfsTer59 | frameshift_variant | 6/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.925_931del | p.Pro309LysfsTer59 | frameshift_variant | 6/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000395 AC: 6AN: 151800Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251216Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135774
GnomAD4 exome AF: 0.00000618 AC: 9AN: 1456906Hom.: 0 AF XY: 0.00000414 AC XY: 3AN XY: 724748
GnomAD4 genome ? AF: 0.0000395 AC: 6AN: 151800Hom.: 0 Cov.: 32 AF XY: 0.0000809 AC XY: 6AN XY: 74132
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:4
Pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Pathogenic, criteria provided, single submitter | curation;literature only | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Mar 01, 2016 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1997 | - - |
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Familial hypercholesterolemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2019 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). This variant has been observed to segregate with familial hypercholesterolemia in multiple families (PMID: 1634609, 9409302). This variant is also known as a founder mutation FH-North Karelia in the literature. ClinVar contains an entry for this variant (Variation ID: 3729). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Pro309Lysfs*59) in the LDLR gene. It 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