ClinVar Genomic variation as it relates to human health

The NM_000527.4(LDLR):c.1774G>A (p.Gly592Arg) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, PP3, PS4_Supportign and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00009799 (0.0098%) in South Asian exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. PM5 - 1 other missense variant in the same codon, NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu) - classified as Pathogenic by the FH VCEP, so PM5 is met. PP3 - REVEL = 0.951. It is above 0.75, so PP3 is met. PS4_supporting - variant meets PM2 and was identified in 3 index cases with Dutch Lipid Clinic Scoring : Definite FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (Accession: SCV000583882.1 in ClinVar), so PS4_Supporting is met. PP4 - variant meets PM2 and was identified in 3 index cases with clinical FH criteria (please see PS4 for details), so PP4 is met.

subjects mutated among 2600 FH index cases screened = 2 / Other mutation at same codon/software prediction damaging

The frequency of this variant in the general population, 0.000098 (3/30616 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with familial hypercholesterolemia (PMIDs: 35910211 (2022), 33740630 (2021), 27932355 (2017)) and coronary artery disease (CAD) (PMID: 27050191 (2016)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 592 of the LDLR protein (p.Gly592Arg). This variant is present in population databases (rs763147599, gnomAD 0.01%). This missense change has been observed in individual(s) with hypercholesterolemia (PMID: 27932355, 33740630, 35910211). This variant is also known as c.1393G>A (p.Gly465Arg). ClinVar contains an entry for this variant (Variation ID: 373769). 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 disrupts the p.Gly592 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15864114, 20663204, 21310417, 21925044, 23375686, 26238499). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

This missense variant (also known as p.Gly571Arg in the mature protein and as p.Gly465Arg based on a different transcript NM_001195803.2) replaces glycine with arginine at codon 592 in the fifth LDLR type B repeat of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in eight individuals affected with familial hypercholesterolemia including one homozygote with premature coronary artery disease (PMID: 27932355, 33732287, 35910211, ClinVar SCV000503411.1, SCV002568019.1). This variant has also been observed in two unaffected individuals (PMID: 27050191, 35910211). This variant has been identified in 4/251478 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Gly592Glu, is known to cause disease (Clinvar variation ID:161271), indicating that glycine at this position is important for the protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.

proposed classification - variant undergoing re-assessment, contact laboratory

The p.G592R variant (also known as c.1774G>A), located in coding exon 12 of the LDLR gene, results from a G to A substitution at nucleotide position 1774. The glycine at codon 592 is replaced by arginine, an amino acid with dissimilar properties. In a study investigating the impact familial hypercholesterolemia (FH) mutations have on coronary artery disease (CAD) risk, this alteration was reported in a individual without CAD, but clinical details on individual cholesterol levels were limited (Khera AV et al. J. Am. Coll. Cardiol. 2016;67:2578-89). One of the most common disease-causing mutations in LDLR, p.G592E, has been described in the same codon (Tichý L et al. Atherosclerosis. 2012;223:401-8). Based on data from ExAC, the A allele has an overall frequency of less than 0.01% (3/106204). 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.

The LDLR c.1774G>A variant is predicted to result in the amino acid substitution p.Gly592Arg. This variant has been reported in the heterozygous state in individuals with hypercholesterolemia (reported as c.1393G>A in Table S3, Li et al. 2017. PubMed ID: 27932355; Table S3, Leren et al. 2021. PubMed ID: 33740630; Diboun et al. 2022. PubMed ID: 35910211) and reported in two individuals from the Homozygous Familial Hypercholesterolemia (HoFH) International Clinical Collaborators registry (Table S3, Tromp et al. 2022. PubMed ID: 35101175). It has also been reported in an unaffected individual (Online table 4, Khera et al. 2016. PubMed ID: 27050191). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD. Another nucleotide change affecting this amino acid (p.Gly592Glu) has been reported in individuals with familial hypercholesterolemia (Hobbs et al. 1992. PubMed ID: 1301956). This variant is interpreted as likely pathogenic.