Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Cardiovascular Research Group, |
RCV000505209 | SCV000599362 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | curation | |
Laboratory of molecular diagnosis of dyslipidemias, |
RCV000505209 | SCV001653623 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2021-05-24 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002323869 | SCV002610167 | pathogenic | Cardiovascular phenotype | 2018-07-20 | criteria provided, single submitter | clinical testing | The p.C377F pathogenic mutation (also known as c.1130G>T), located in coding exon 8 of the LDLR gene, results from a G to T substitution at nucleotide position 1130. The cysteine at codon 377 is replaced by phenylalanine, an amino acid with highly dissimilar properties, and is located in the EGF-like 2 domain. Pathogenic LDLR alterations 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 individual with FH, and functional studies demonstrated a significant reduction in LDLR activity (Romano M et al. J. Lipid Res., 2011 Nov;52:2095-100). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of EGF-like 2 domain (Ambry internal data). Alternate amino acid substitutions at this position, including p.C377S (c.1130G>C), p.C377G (c.1129T>G) and p.C377Y (c.1130G>A) have also been reported in individuals with FH (Ekström U et al. Eur. J. Clin. Invest. 1998 Sep;28:740-7; Bertolini S et al. Atherosclerosis. 2013 Apr;227: 342-8; Wu WF et al. PLoS ONE 2014 Apr; 9:e94697). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |