19-11113433-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000527.5(LDLR):c.1342C>T(p.Gln448Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,846 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 (★★). Synonymous variant affecting the same amino acid position (i.e. Q448Q) has been classified as Likely benign. 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.1342C>T | p.Gln448Ter | stop_gained | 9/18 | ENST00000558518.6 | |
MIR6886 | NR_106946.1 | upstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1342C>T | p.Gln448Ter | stop_gained | 9/18 | 1 | NM_000527.5 | P3 | |
MIR6886 | ENST00000619864.1 | upstream_gene_variant |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152164Hom.: 0 Cov.: 29
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251242Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135850
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461682Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727144
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152164Hom.: 0 Cov.: 29 AF XY: 0.0000135 AC XY: 1AN XY: 74328
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:8
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The p.Gln448Ter variant in LDLR has been reported in 21 individuals (including 20 Spanish and 1 Mexican individual) with Familial Hypercholesterolemia (PMID: 21722902, 15241806, 27784735), and has been identified in 0.005644% (2/35434) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs879254871). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported pathogenic in ClinVar (Variation ID: 251798). This nonsense variant leads to a premature termination codon at position 448, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in Familial Hypercholesterolemia. The phenotype of 3 individuals homozygous for this variant is highly specific for Familial Hypercholesterolemia (PMID: 15241806, 27784735). Individuals who are homozygous for pathogenic variants are known to have a more severe phenotype than heterozygous individuals. In summary, this variant meets criteria to be classified as pathogenic for Familial Hypercholesterolemia in an autosomal dominant manner based on the predicted impact of the variant and multiple occurrences in individuals with Familial Hypercholesterolemia. ACMG/AMP Criteria applied: PVS1, PS4, PP4 (Richards 2015). - |
Pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Pathogenic, criteria provided, single submitter | research | Iberoamerican FH Network | Mar 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | 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 | subject mutated among 2600 FH index cases screened = 1 - |
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 | U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Mar 30, 2017 | - - |
Familial hypercholesterolemia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 06, 2023 | This sequence change creates a premature translational stop signal (p.Gln448*) 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 (no rsID available, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 15241806, 28993407, 30586733). This variant is also known as p.Q427X. ClinVar contains an entry for this variant (Variation ID: 251798). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 29, 2019 | Variant summary: LDLR c.1342C>T (p.Gln448X) 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. The variant allele was found at a frequency of 4e-06 in 251242 control chromosomes (gnomAD). c.1342C>T has been reported in the literature in multiple individuals affected with Autosomal Dominant Hypercholesterolemia as well as Homozygous Familial Hypercholesterolemia (e.g. Ahmad_2012, Alonso_2016, Martin-Campos_2018). These data indicate that the variant is very likely to be associated with disease. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 02, 2016 | The p.Q448* variant (also known as c.1342C>T), located in coding exon 9 of the LDLR gene, results from a C to T substitution at nucleotide position 1342. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This alteration has been reported in association with familial hypercholesterolemia and is noted as a common mutation in Spanish populations (Mozas P, Hum. Mutat. 2004 Aug; 24(2):187; Vaca G, Atherosclerosis 2011 Oct; 218(2):391-6; Ahmad Z, Circ Cardiovasc Genet 2012 Dec; 5(6):666-75; Alonso R, J. Am. Coll. Cardiol. 2014 May; 63(19):1982-9; Jannes CE, Atherosclerosis 2015 Jan; 238(1):101-7. In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at