ClinVar

Description

The c.324_325delGTinsTC pathogenic mutation, located in coding exon 4 of the LDLR gene, results from an in-frame deletion of GT and insertion of TC at nucleotide positions 324 to 325. This results in the substitution of the cysteine residue for an arginine residue at codon 109, 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). Internal structural analysis indicates this variant eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 3 domain (Ambry internal data). This variant, which is also known as p.C88R, has been reported in individuals with familial hypercholesterolemia (FH) (Heath KE et al. Eur J Hum Genet, 2001 Apr;9:244-52; Chmara M et al. J Appl Genet, 2010;51:95-106; Sturm AC et al. JAMA Cardiol, 2021 Aug;6:902-909; Rutkowska L et al. Genes (Basel), 2022 Jun;13:[ePub ahead of print]). Another nucleotide change at the same codon that results in the same amino acid change, c.325T>C (p.C109R), which is also known as FH Munster-1, has been reported in individuals with familial hypercholesterolimia (FH) from a number of ethnic groups (Hobbs HH et al. Hum Mutat. 1992;1:445-66; Fouchier SW et al. Hum Mutat. 2005;26:550-6; Robles-Osorio L et al. Arch Med Res. 2006;37:102-8; Tichý L et al. Atherosclerosis. 2012;223:401-8). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.