Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| LDLR- |
RCV000237561 | SCV000295171 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Cardiovascular Research Group, |
RCV000237561 | SCV000599358 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | curation | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000586287 | SCV000697183 | pathogenic | Familial hypercholesterolemia | 2017-07-26 | criteria provided, single submitter | clinical testing | Variant summary: The LDLR c.1056C>G (p.Cys352Trp) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. The variant of interest has not been found in a large, broad control population, ExAC in 120928 control chromosomes. This variant was reported in multiple patients with familial hypercholesterolemia (FH), including a homozygous patient whose phenotype was more severe than the heterozygous patients (Bertolini_Atherosclerosis_2013, Fouchier_HG_2001), including . A functional study suggested that the variant causes a defective LDL receptor, though the data was not provided for independent assessment (Bertolini_Atherosclerosis_2013). In addition, one clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic. |
| Brunham Lab, |
RCV000237561 | SCV001432585 | pathogenic | Hypercholesterolemia, familial, 1 | 2019-01-23 | criteria provided, single submitter | research | |
| Laboratory of molecular diagnosis of dyslipidemias, |
RCV000237561 | SCV001653617 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2021-05-24 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002401933 | SCV002712277 | pathogenic | Cardiovascular phenotype | 2019-09-23 | criteria provided, single submitter | clinical testing | The p.C352W pathogenic mutation (also known as c.1056C>G), located in coding exon 7 of the LDLR gene, results from a C to G substitution at nucleotide position 1056. The cysteine at codon 352 is replaced by tryptophan, an amino acid with highly dissimilar properties, and is located in an EGF-like domain. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). This particular cysteine alteration (also referred to as C331W and FH Avellino-1) has been reported in the homozygous state in a pediatric patient reported to have a clinical diagnosis of homozygous familial hypercholesterolemia (FH) and significantly reduced LDL-receptor activity; however, experimental data were not shown (Bertolini S et al. Arterioscler. Thromb. Vasc. Biol., 1999;19:408-18). This variant has been detected in additional individuals from FH cohorts (Lombardi MP et al. Clin. Genet., 2000;57:116-24; Van Gaal LF et al. Mol. Cell. Probes, 2001;15:329-36; Bertolini S et al. Atherosclerosis, 2013;227:342-8; Gabová D et al. Physiol Res, 2017;66:75-84). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the EGF-like 1 domain (Ambry internal data). In addition, other variants affecting this codon (e.g., p.C352Y and p.C352S) have also been reported in association with FH (Magaña Torres MT et al. J Clin Lipidol. 2014;8:525-7; Medeiros AM et al. Genet. Med. 2016;18:316-24). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000237561 | SCV000606302 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |