ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1033C>T (p.Gln345Ter)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211644 SCV000295153 pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000211644 SCV000322923 pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research 0/190 non-FH alleles
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000211644 SCV000503284 pathogenic Hypercholesterolemia, familial, 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 3 , family member = 1 with co-segregation / previously described in association with FH
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000211644 SCV000588542 pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001260435 SCV001437432 pathogenic Familial hypercholesterolemia 2020-09-16 criteria provided, single submitter clinical testing 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.
Ambry Genetics RCV002390566 SCV002699179 pathogenic Cardiovascular phenotype 2022-08-19 criteria provided, single submitter clinical testing 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001260435 SCV003443871 pathogenic Familial hypercholesterolemia 2023-07-17 criteria provided, single submitter clinical testing 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 Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211644 SCV000268594 pathogenic Hypercholesterolemia, familial, 1 2008-07-22 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000211644 SCV000606297 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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