ClinVar Genomic variation as it relates to human health

The p.C377Y pathogenic mutation (also known as c.1130G>A), located in coding exon 8 of the LDLR gene, results from a G to A substitution at nucleotide position 1130. The cysteine at codon 377 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in the EGF-like B domain. This alteration, also described as p.C356Y, has been identified in several individuals from familial hypercholesterolemia (FH) cohorts (Ekström U et al. Eur. J. Clin. Invest. 1998;28:740-7, Mozas P et al. Hum. Mutat. 2004;24:187, Vandrovcova J et al. Genet. Med. 2013;15:948-57). In addition, alterations involving the same amino acid position, p.C377S (c.1130G>C), p.C377G (c.1129T>G) and p.C377F (c.1130G>T) have been reported in individuals with FH (Bertolini S et al. Atherosclerosis. 2013;227: 342-8, Wu WF et al. PLoS ONE 2014; 9:e94697, Romano M et al, J. Lipid Res. 2011; 52:2095-100). 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 (Villéger L. Hum Mutat. 2002;20(2):81-7). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of EGF-like 2 domain (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

The LDLR c.1130G>A; p.Cys377Tyr variant (rs879254801), also known as Cys356Tyr in legacy nomenclature, is reported in the literature in the heterozygous and compound heterozygous states in numerous individuals affected with familial hypercholesterolemia (Ekstrom 1998, Benedek 2021, Gabcova 2017, Marco-Benedi 2022, Rieck 2020, Wang 2018). This variant is also reported in ClinVar (Variation ID: 251681) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other amino acid substitutions at this codon (Arg, Gly, Phe, Ser) have been reported in individuals with familial hypercholesterolemia and are considered to be disease causing (Bertolini 2020, Bertolini 2013, Gabcova 2017, Wu 2014). Computational analyses predict that this variant is deleterious (REVEL: 0.984). Based on the available information, this variant is considered to be pathogenic. References: Ekstrom U et al. Mutations in the low-density lipoprotein receptor gene in Swedish familial hypercholesterolaemia patients: clinical expression and treatment response. Eur J Clin Invest. 1998 Sep;28(9):740-7. PMID: 9767373. Benedek P et al. Founder effects facilitate the use of a genotyping-based approach to molecular diagnosis in Swedish patients with familial hypercholesterolaemia. J Intern Med. 2021 Aug;290(2):404-415. PMID: 33955087. Bertolini S et al. Italian Study Group of Homozygous Familial Hypercholesterolemia. Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features. Atherosclerosis. 2020 Nov;312:72-78. PMID: 32977124. Bertolini S et al. Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. Atherosclerosis. 2013 Apr;227(2):342-8. PMID: 23375686. Gabcova D et al. The molecular genetic background of familial hypercholesterolemia: data from the Slovak nation-wide survey. Physiol Res. 2017 Mar 31;66(1):75-84. PMID: 27824480. Marco-Benedi V et al. Lipoprotein(a) in hereditary hypercholesterolemia: Influence of the genetic cause, defective gene and type of mutation. Atherosclerosis. 2022 May;349:211-218. PMID: 34456049. Rieck L et al. Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia. Clin Genet. 2020 Nov;98(5):457-467. PMID: 32770674. Wang F et al. Genetic analysis in a compound heterozygote family with familial hypercholesterolemia. Mol Med Rep. 2018 Jun;17(6):8439-8449. PMID: 29693183. Wu WF et al. Use of targeted exome sequencing in genetic diagnosis of Chinese familial hypercholesterolemia. PLoS One. 2014 Apr 10;9(4):e94697. PMID: 24722143.

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 377 of the LDLR protein (p.Cys377Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9767373, 23680767, 27824480, 32770674). This variant is also known as p.C356Y. ClinVar contains an entry for this variant (Variation ID: 251681). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). This variant disrupts the p.Cys377 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24722143, 29693183). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.