rs875989913
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000527.5(LDLR):c.1033C>T(p.Gln345Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,424 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.1033C>T | p.Gln345Ter | stop_gained | 7/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1033C>T | p.Gln345Ter | stop_gained | 7/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461424Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727022
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:6
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital | Jul 22, 2008 | - - |
Pathogenic, criteria provided, single submitter | research | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Mar 01, 2016 | 0/190 non-FH alleles - |
Pathogenic, criteria provided, single submitter | research | Laboratory of Genetics and Molecular Cardiology, University of São Paulo | Mar 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix | Dec 16, 2016 | subjects mutated among 2600 FH index cases screened = 3 , family member = 1 with co-segregation / previously described in association with FH - |
Familial hypercholesterolemia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 16, 2020 | Variant summary: LDLR c.1033C>T (p.Gln345X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251072 control chromosomes (gnomAD). c.1033C>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Day_1997, Bourbon_2008, Hooper_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 17, 2023 | This sequence change creates a premature translational stop signal (p.Gln345*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 9259195). This variant is also known as Q324X. ClinVar contains an entry for this variant (Variation ID: 226341). For these reasons, this variant has been classified as Pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 19, 2022 | The p.Q345* pathogenic mutation (also known as c.1033C>T), located in coding exon 7 of the LDLR gene, results from a C to T substitution at nucleotide position 1033. This changes the amino acid from a glutamine to a stop codon within coding exon 7. This alteration, which is also known as p.Q324*, has been reported in individuals with familial hypercholesterolemia (FH) (Day IN et al. Hum Mutat, 1997;10:116-27; Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42; Taylor A et al. Clin Genet, 2010 Jun;77:572-80; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, 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