ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2431A>T (p.Lys811Ter)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237271 SCV000296007 pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000237271 SCV000588666 pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Labcorp Genetics (formerly Invitae), Labcorp RCV000816738 SCV000957260 pathogenic Familial hypercholesterolemia 2023-05-31 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 252336). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This premature translational stop signal has been observed in individuals with hypercholesterolemia in a family and in several unrelated affected individuals (PMID: 7583548, 19013141, 21872251). It has also been observed to segregate with disease in related individuals. This variant is also known as K790X. For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Lys811*) 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).
Ambry Genetics RCV002450751 SCV002737520 pathogenic Cardiovascular phenotype 2020-09-30 criteria provided, single submitter clinical testing The p.K811* pathogenic mutation (also known as c.2431A>T), located in coding exon 17 of the LDLR gene, results from an A to T substitution at nucleotide position 2431. This changes the amino acid from a lysine to a stop codon within coding exon 17. This alteration (also reported with legacy nomenclature as p.K790*) is one of the most common LDLR mutations found in Japan, and it has been detected in the heterozygous, compound heterozygous, and homozygous state in individuals with familial hypercholesterolemia (Maruyama T et al. Arterioscler. Thromb. Vasc. Biol., 1995 Oct;15:1713-8; Yu W et al. Atherosclerosis, 2002 Dec;165:335-42; Mabuchi H et al. Atherosclerosis, 2011 Feb;214:404-7). It has also been reported to segregate with disease in at least one family (Tada H et al. Atherosclerosis, 2011 Dec;219:663-6). Lymphocytes derived from patients heterozygous with this alteration exhibited approximately 55% of control LDLR activity (Tada H et al. Clin. Chim. Acta, 2009 Feb;400:42-7). In addition to the clinical data presented in the literature, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000816738 SCV004240929 pathogenic Familial hypercholesterolemia 2023-12-12 criteria provided, single submitter clinical testing Variant summary: LDLR c.2431A>T (p.Lys811X) 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 was absent in 251434 control chromosomes. c.2431A>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia and is one of the most common Japanese mutations (eg. Tada_2020, etc). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237271 SCV000606652 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.