Total submissions: 20
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000003884 | SCV000295499 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Robarts Research Institute, |
RCV000003884 | SCV000484683 | likely pathogenic | Familial hypercholesterolemia 1 | criteria provided, single submitter | clinical testing | ||
Centre de Génétique Moléculaire et Chromosomique, |
RCV000003884 | SCV000503365 | likely pathogenic | Familial hypercholesterolemia 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 | Familial hypercholesterolemia 1 | 2016-11-05 | criteria provided, single submitter | clinical testing | |
U4M - |
RCV000003884 | SCV000583848 | pathogenic | Familial hypercholesterolemia 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
Laboratory of Genetics and Molecular Cardiology, |
RCV000003884 | SCV000588586 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | research | |
Fundacion Hipercolesterolemia Familiar | RCV000003884 | SCV000607607 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | research | |
Integrated 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 | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | research | |
Color | RCV000587718 | SCV000909173 | pathogenic | Familial hypercholesterolemia | 2019-09-30 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000587718 | SCV000940009 | likely pathogenic | Familial hypercholesterolemia | 2019-12-30 | criteria provided, single submitter | clinical testing | This sequence change replaces valine with methionine at codon 523 of the LDLR protein (p.Val523Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs28942080, ExAC 0.006%). This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 2088165, 23375686, 21865347, 22294733, 14974088, 15256764, 21310417, 25463123, 27765764). This variant is also known as V502M in the literature. ClinVar contains an entry for this variant (Variation ID: 3696). This variant has been reported not to substantially affect LDLR protein 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
Laboratory for Molecular Medicine, |
RCV000825622 | SCV000966974 | pathogenic | Homozygous familial hypercholesterolemia | 2019-03-26 | 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). In vitro functional studies provide some evidence that the heterozygous p.Val523Met variant may impact protein function (Romano 2011). It has been reported in ClinVar (Variation ID: 3696) and has also been identified in 1/30782 South Asian and 2/111654 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28942080). In summary, this variant meets criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based upon proband count, absence from controls, and functional studies. The ACMG/AMP Criteria applied: PS4, PM2, PS3_Supporting, PM3_Strong. |
Institute of Human Genetics, |
RCV000003884 | SCV001430013 | pathogenic | Familial hypercholesterolemia 1 | 2018-03-16 | criteria provided, single submitter | clinical testing | |
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV000003884 | SCV001433508 | pathogenic | Familial hypercholesterolemia 1 | 2019-04-29 | criteria provided, single submitter | clinical testing | |
Institute of Human Genetics, |
RCV000003884 | SCV001440422 | likely pathogenic | Familial hypercholesterolemia 1 | 2019-01-01 | criteria provided, single submitter | clinical testing | |
OMIM | RCV000003884 | SCV000024049 | pathogenic | Familial hypercholesterolemia 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 | Familial hypercholesterolemia 1 | 2013-01-23 | no assertion criteria provided | clinical testing | |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000003884 | SCV000606453 | pathogenic | Familial hypercholesterolemia 1 | no assertion criteria provided | research | ||
Broad Institute Rare Disease Group, |
RCV000587718 | SCV001422746 | likely pathogenic | Familial hypercholesterolemia | 2020-01-22 | no assertion criteria provided | 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). |