rs879254867
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000527.5(LDLR):c.1329G>A(p.Trp443Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000527.5 stop_gained
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1329G>A | p.Trp443Ter | stop_gained | 9/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1329G>A | p.Trp443Ter | stop_gained | 9/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 29
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461678Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727132
GnomAD4 genome ? Cov.: 29
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | research | Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia | May 11, 2019 | - - |
Pathogenic, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | Mar 01, 2016 | - - |
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 16, 2017 | The p.W443* pathogenic mutation (also known as c.1329G>A), located in coding exon 9 of the LDLR gene, results from a G to A substitution at nucleotide position 1329. This changes the amino acid from a tryptophan to a stop codon within coding exon 9. This alteration (also referred to by legacy nomenclature, p.W422*) has been reported in individuals with familial hypercholesterolemia (Zakharova FM et al. BMC Med. Genet., 2005 Feb;6:6; Abifadel M et al. Hum. Mutat., 2009 Jul;30:E682-91). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at