Submissions for variant NM_000527.5(LDLR):c.1342C>T (p.Gln448Ter)

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238528	SCV000295378	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000238528	SCV000503336	pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000238528	SCV000583823	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000238528	SCV000588573	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000238528	SCV000607589	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Iberoamerican FH Network	RCV000238528	SCV000748055	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Invitae	RCV001053274	SCV001217530	pathogenic	Familial hypercholesterolemia	2023-09-06	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001053274	SCV001363969	pathogenic	Familial hypercholesterolemia	2019-10-29	criteria provided, single submitter	clinical testing	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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000238528	SCV001422789	pathogenic	Hypercholesterolemia, familial, 1	2020-01-22	criteria provided, single submitter	curation	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).
Ambry Genetics	RCV002379065	SCV002694575	pathogenic	Cardiovascular phenotype	2016-03-02	criteria provided, single submitter	clinical testing	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.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238528	SCV000606402	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research