Total submissions: 26
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000003884 | SCV000295499 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Robarts Research Institute, |
RCV000003884 | SCV000484683 | likely pathogenic | Hypercholesterolemia, familial, 1 | criteria provided, single submitter | clinical testing | ||
Centre de Génétique Moléculaire et Chromosomique, |
RCV000003884 | SCV000503365 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subjects mutated among 2600 FH index cases screened = 2 , family members = 4 with co-segregation / FH-Koweit-Bari,15 to 30% LDLR Activity/Software predictions: Conflicting |
Molecular Genetics Laboratory, |
RCV000003884 | SCV000540825 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-11-05 | criteria provided, single submitter | clinical testing | |
U4M - |
RCV000003884 | SCV000583848 | pathogenic | Hypercholesterolemia, familial, 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
Laboratory of Genetics and Molecular Cardiology, |
RCV000003884 | SCV000588586 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
Fundacion Hipercolesterolemia Familiar | RCV000003884 | SCV000607607 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000587718 | SCV000697201 | pathogenic | Familial hypercholesterolemia | 2016-08-09 | criteria provided, single submitter | clinical testing | Variant summary: The LDLR c.1567G>A (p.Val523Met) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/120764 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0010005). The variant has been reported in numerous affected individuals in the literature in the homozygous and compound heterozygous state. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. |
Iberoamerican FH Network | RCV000003884 | SCV000748098 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
Color Diagnostics, |
RCV000587718 | SCV000909173 | pathogenic | Familial hypercholesterolemia | 2019-09-30 | criteria provided, single submitter | clinical testing | This missense variant (also known as p.Val502Met in the mature protein and as FH Kuwait, FH Bari-2) replaces valine with methionine at codon 523 in the third LDLR type B repeat of the EGF precursor homology domain 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has shown that this variant causes LDLR recycling defect (PMID: 2088165) and results in a significantly reduced LDLR activity in cells from homozygous individuals (PMID: 9974426). This variant has been reported in over 15 European individuals affected with familial hypercholesterolemia (PMID: 7616128, 12436241, 15241806, 20045108, 26892515), including several homozygous and compound heterozygous individuals (PMID: 9974426, 30795984). This variant has been identified in 3/251336 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. |
Invitae | RCV000587718 | SCV000940009 | pathogenic | Familial hypercholesterolemia | 2024-01-05 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 523 of the LDLR protein (p.Val523Met). This variant is present in population databases (rs28942080, gnomAD 0.003%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 2088165, 14974088, 15256764, 21310417, 21865347, 22294733, 23375686, 25463123, 27765764). This variant is also known as V502M. ClinVar contains an entry for this variant (Variation ID: 3696). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect LDLR function (PMID: 25647241). This variant disrupts the p.Val523 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. For these reasons, this variant has been classified as Pathogenic. |
Laboratory for Molecular Medicine, |
RCV000825622 | SCV000966974 | pathogenic | Homozygous familial hypercholesterolemia | 2020-05-28 | criteria provided, single submitter | clinical testing | The p.Val523Met variant in LDLR (also referred as p.Val502Met, FH Kuwait, and FH Bari-2) has been reported in >100 heterozygous individuals with hypercholesterolemia as well as in at least 3 homozygous individuals and 3 compound heterozygous individuals with homozygous familial hypercholesterolemia (Hobbs 1990, Tichy 2012, Bertolini 2013, Wang 2016, Sánchez-Hernández 2016, Pirillo 2017). This variant also segregated with homozygous familial hypercholesterolemia in 1 homozygous relative (Bertolini 2013). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 3696) and has been identified in 0.003% (1/30782) of South Asian and 0.002% (2/111654) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the heterozygous p.Val523Met variant may impact protein function (Romano 2011). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP Criteria applied: PS4, PM2, PS3_Supporting, PM3_Strong. |
Broad Center for Mendelian Genomics, |
RCV000587718 | SCV001422746 | likely pathogenic | Familial hypercholesterolemia | 2020-01-22 | criteria provided, single submitter | curation | The p.Val523Met variant in LDLR has been reported in at least 15 individuals with familial hypercholesterolemia (PMID: 15241806, 25463123, 15199436, 9974426, 7616128, 2088165, 21310417, 26892515, 12436241), and has been identified in 0.003% (1/30616) of South Asian chromosomes and 0.002% (2/113644) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28942080). This variant has also been reported in ClinVar as pathogenic or likely pathogenic (Variation ID: 3696). In vitro functional studies provide some evidence that the p.Val523Met variant may slightly impact protein function (PMID: 25647241, 21865347). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS4, PP3, PS3_supporting (Richards 2015). |
Institute Of Human Genetics Munich, |
RCV000003884 | SCV001430013 | pathogenic | Hypercholesterolemia, familial, 1 | 2018-03-16 | criteria provided, single submitter | clinical testing | |
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV000003884 | SCV001433508 | pathogenic | Hypercholesterolemia, familial, 1 | 2019-04-29 | criteria provided, single submitter | clinical testing | |
Institute of Human Genetics, |
RCV000003884 | SCV001440422 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2019-01-01 | criteria provided, single submitter | clinical testing | |
Laboratory of molecular diagnosis of dyslipidemias, |
RCV000003884 | SCV001653640 | pathogenic | Hypercholesterolemia, familial, 1 | 2021-05-24 | criteria provided, single submitter | clinical testing | Reduced activity, in stimulated T-lymphocytes and EBV-transformed B-lymphocytes. |
Revvity Omics, |
RCV000003884 | SCV002017132 | pathogenic | Hypercholesterolemia, familial, 1 | 2022-04-21 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002399309 | SCV002708769 | pathogenic | Cardiovascular phenotype | 2022-07-07 | criteria provided, single submitter | clinical testing | The p.V523M pathogenic mutation (also known as c.1567G>A), located in coding exon 10 of the LDLR gene, results from a G to A substitution at nucleotide position 1567. The valine at codon 523 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in the homozygous and heterozygous states in multiple individuals with familial hypercholesterolemia from various ethnic groups (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Lombardi P et al. J. Lipid Res., 1995 Apr;36:860-7; Bertolini S et al. Arterioscler. Thromb. Vasc. Biol., 1999 Feb;19:408-18; Amsellem S et al. Hum. Genet., 2002 Dec;111:501-10; Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Mozas P et al. Hum. Mutat., 2004 Aug;24:187; Dušková L et al. Atherosclerosis, 2011 May;216:139-45; Mollaki V et al. Atherosclerosis, 2014 Dec;237:798-804; Sharifi M et al. Metab. Clin. Exp., 2016 Mar;65:48-53; (Luirink IK et al. J Clin Lipidol, 2018 Dec;[Epub ahead of print]). In addition, a number of studies have reported this alteration to attenuate LDLR activity (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Bertolini S et al. Arterioscler. Thromb. Vasc. Biol., 1999 Feb;19:408-18; Romano M et al. J. Lipid Res., 2011 Nov;52:2095-100). Furthermore, internal structural analysis indicates this alteration to be structurally disruptive (Lo Surdo P et al. EMBO Rep. 2011 Dec;12(12):1300-5). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Institute of Human Genetics, |
RCV000003884 | SCV002822895 | likely pathogenic | Hypercholesterolemia, familial, 1 | criteria provided, single submitter | clinical testing | ||
OMIM | RCV000003884 | SCV000024049 | pathogenic | Hypercholesterolemia, familial, 1 | 2014-08-27 | no assertion criteria provided | literature only | |
Dept. |
RCV000161992 | SCV000189567 | not provided | not provided | no assertion provided | in vitro | ||
Cardiovascular Genetics Laboratory, |
RCV000003884 | SCV000268622 | pathogenic | Hypercholesterolemia, familial, 1 | 2013-01-23 | no assertion criteria provided | clinical testing | |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000003884 | SCV000606453 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research | ||
Clinical Genetics, |
RCV000161992 | SCV001923962 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Diagnostic Laboratory, |
RCV000161992 | SCV001962947 | pathogenic | not provided | no assertion criteria provided | clinical testing |