Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000237283 | SCV000294725 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Brunham Lab, |
RCV000237283 | SCV001432651 | pathogenic | Hypercholesterolemia, familial, 1 | 2019-06-05 | criteria provided, single submitter | research | |
Ambry Genetics | RCV002338778 | SCV002635279 | likely pathogenic | Cardiovascular phenotype | 2019-01-17 | criteria provided, single submitter | clinical testing | The p.C155R variant (also known as c.463T>C), located in coding exon 4 of the LDLR gene, results from a T to C substitution at nucleotide position 463. The cysteine at codon 155, located at LDLR class A repeat 4, is replaced by arginine, an amino acid with highly dissimilar properties. 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 variant was reported in an FH cohort with limited clinical details provided (Yu W et al. Atherosclerosis, 2002 Dec;165:335-42). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 4 (Ambry internal data). Alternate amino acid substitutions at this position, including p.C155G (legacy p.C134G) and p.C155F, have been reported in individuals with FH (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Lombardi MP et al. Clin. Genet., 2000 Feb;57:116-24; van der Graaf A et al. Circulation, 2011 Mar;123:1167-73). This amino acid position is highly conserved in available vertebrate species. 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, |
RCV000237283 | SCV000606126 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |