ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1702C>G (p.Leu568Val)

dbSNP: rs746959386
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237626 SCV000295587 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute, Western University RCV000237626 SCV000484763 likely pathogenic Hypercholesterolemia, familial, 1 criteria provided, single submitter clinical testing
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237626 SCV000599380 pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter curation
Invitae RCV000799671 SCV000939345 pathogenic Familial hypercholesterolemia 2022-12-11 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 568 of the LDLR protein (p.Leu568Val). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu568 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 20809525), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. ClinVar contains an entry for this variant (Variation ID: 251976). This variant is also known as p.L547V. This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 10447263, 18718593, 25962062, 26510755). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals.
Color Diagnostics, LLC DBA Color Health RCV000799671 SCV001358588 likely pathogenic Familial hypercholesterolemia 2020-01-31 criteria provided, single submitter clinical testing This missense variant (also known as p.Leu547Val in the mature protein) replaces leucine with valine at codon 568 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Computational splicing tools suggest that this variant may impact RNA splicing by activating a new splice donor site. This splice prediction has not been investigated in published RNA studies. It has been shown that this variant segregates with disease in 3 related individuals from a family affected with familial hypercholesterolemia (PMID: 26510755). This variant has been reported in multiple Japanese individuals affected with familial hypercholesterolemia (PMID: 10447263, 18718593, 26632531, 31491741) and is thought to occur at 3.4% of affected individuals, compared to 0.08% minor allele frequency in the general population in Japan (PMID: 18718593). This variant has also been identified in a Korean individual affected with familial hypercholesterolemia (PMID: 26343872). Carriers of this variant show very mild clinical phenotype due to ~75% residual LDL binding activity of the mutant protein (PMID: 18718593). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Mendelics RCV000237626 SCV002516654 pathogenic Hypercholesterolemia, familial, 1 2022-05-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV002401941 SCV002710169 likely pathogenic Cardiovascular phenotype 2022-03-11 criteria provided, single submitter clinical testing The p.L568V variant (also known as c.1702C>G), located in coding exon 11 of the LDLR gene, results from a C to G substitution at nucleotide position 1702. The leucine at codon 568 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported as a heterozygote and compound heterozygote in familial hypercholesterolemia (FH) cohorts and has been reported in multiple family members in an affected family (Hattori H et al. Hum Mutat, 1999;14:87; Ohshiro T et al. J Atheroscler Thromb, 2010 Oct;17:1113; Miyagi Y et al. J Atheroscler Thromb, 2016 Oct;23:112-7; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909; Nagahara K et al. J Atheroscler Thromb, 2021 May). This variant is also considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237626 SCV000606488 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.