ClinVar Miner

Submissions for variant NM_174936.4(PCSK9):c.45GCT[8] (p.Leu23dup)

dbSNP: rs35574083
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 17
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Preventiongenetics, part of Exact Sciences RCV000223787 SCV000316576 likely benign not specified criteria provided, single submitter clinical testing
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000256353 SCV000323028 benign Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research MAF = 9% in 100 subjects with average plasma cholesterol
Color Diagnostics, LLC DBA Color Health RCV000256353 SCV000690984 benign Hypercholesterolemia, familial, 1 2017-07-07 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000625171 SCV000743995 benign Hypercholesterolemia, autosomal dominant, 3 2016-04-26 criteria provided, single submitter clinical testing
Iberoamerican FH Network RCV000256353 SCV000748065 benign Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Color Diagnostics, LLC DBA Color Health RCV000776608 SCV000912224 benign Familial hypercholesterolemia 2018-05-21 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV000845341 SCV000987387 likely benign not provided criteria provided, single submitter clinical testing
Invitae RCV000625171 SCV001725597 benign Hypercholesterolemia, autosomal dominant, 3 2024-02-01 criteria provided, single submitter clinical testing
GeneDx RCV000845341 SCV001894657 benign not provided 2016-11-15 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 29562810, 30782561, 26687699, 25239117, 23743349, 16619215, 23663650, 20006333)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000845341 SCV002048042 benign not provided 2023-11-29 criteria provided, single submitter clinical testing
Ambry Genetics RCV002354623 SCV002655980 benign Cardiovascular phenotype 2015-12-14 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000845341 SCV004222383 benign not provided 2023-06-20 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223787 SCV000280405 benign not specified 2013-01-30 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. c.63_65dupGCT in PCKS9 (aka c.61_63dupCTG, c.43_44insCTG, L21dup, L10, p.L15_16insL). This is an in-frame duplication of three nucleotides which results in insertion of a leucine in a 9-leucine track. The variant has been seen in at least 8 unrelated cases of familial hypercholesterolemia however it has also been observed at appreciable frequencies in individuals from the general population with normal cholesterol. Noguchi et al (2010) reported that 8 of 55 familial hypercholesterolemia patients without LDLR variants were heterozygous for this variant. No segregation or control data was provided. In total the variant has been seen in the homozygous state in 11 of 822 individuals and in the heterozygous state in 204 of 822 individuals from published reports and publicly available population datasets. The variant is listed in dbSNP as rs35574083 without minor allele frequency data. Another dbSNP entry, rs45454392, also represents a leucine insertion in the same track of leucine repeats, denoted c.44_45insGCT (p.Leu15delinsLeuLeu). These variants are likely synonymous as it would be impossible to know exactly where the insertion occurred in the repeat track and different groups would choose to number at different points in the track, but with both insertions leading to an additional leucine. The latter dbSNP entry includes minor allele frequency data from general populations samples in the Coriell repository with 2/24 African Americans being homozygotes for the insertion and 9/24 African American and 4/23 European individuals noted as heterozygotes. Chen et al (2005) reported allele frequencies for the L9, L10, and L11 variants in the Lipoprotein Coronary Atherosclerosis Study population (LCAS). The sample consistent of 372 35-75yo individuals with LDL-C levels of 115 to 190 mg/dL despite diet and one more coronary lesions of 30-75% stenosis.. Given this selection criteria this cannot be considered a general population sample, however their LDL levels indicate they likely did not have familial hypercholesterolemia. 90/372 individuals studied were heterozygotes for the L10 variant. Yue et al (2006) reported that in a general population sample with normal cholesterol phenotypes 101/403 individuals were heterozygoes for the L10 allele and 9/403 were homozygous. Unfortunately the NHLBI Exome Sequencing Project dataset only reports single nucleotide variation so no data is provided on this variant. Yue et al (2006) found that the variant is associated with lower LDL-C in a Caucasian sample with normal cholesterol. Individuals who had one 9 repeat copy and one 10 repeat copy (i.e. heterozygotes for this variant) had LDL-C that was 10-15 mg/dL lower. They found the 10 repeat variant was an independent predictor of LDL-C. Pisciotta et al (2011) compared total cholesterol LDL-C levels in familial hypercholesterolemia patients who were heterozygous for the 10 repeat variant with those who were homozygous for the wildtype 9 repeat variant and found no differences. However, in the subgroup of individuals treated with statins, the reduction in both total cholesterol and LDL-C was greater in heterozygotes for L10 than in wildtype homozygotes.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000256353 SCV000606673 benign Hypercholesterolemia, familial, 1 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000223787 SCV001740953 benign not specified no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000223787 SCV001926190 benign not specified no assertion criteria provided clinical testing
Cohesion Phenomics RCV000776608 SCV003836771 benign Familial hypercholesterolemia 2023-02-09 no assertion criteria provided clinical testing

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.