ClinVar Genomic variation as it relates to human health

NM_000527.5(LDLR):c.1576C>T (p.Pro526Ser) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4 and PS4_Supportive) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00002326 (0.002%) in European-non Finnish exomes (gnomAD v2.1.1). PP3 - REVEL: 0,952. PP4 - Variant meets PM2. Variant identified in 5 index cases (1 case from Color laboratory with Simon-Broome criteria; 1 case from GeneDx laboratory with Simon Broome criteria; 1 cases from University of British Columbia with DLCN criteria; 2 cases fulfilling Simeon-Broome criteria published in PMID: 9259195). PS4_supporting - Variant meets PM2. Variant identified in 5 index cases.

This missense variant replaces proline with serine at codon 526 in the third LDLR type B repeat of the EGF precursor homology domain of the LDLR protein. This variant is also known as p.Pro505Ser in the mature protein; FH Cincinnati-3. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant interferes with protein transport and significantly affects LDLR biosynthesis or turnover (PMID: 25647241). Another functional study has shown significantly reduced LDLR activity (5-15% of the wild type) in cells from an individual with heterozygous hypercholesterolemia (PMID: 1301956). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 1301956, 9259195, 10208479, 11462246, 27497240, 31345425, 34037665; Color internal data). This variant has been identified in 3/282624 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

subjects mutated among 2600 FH index cases screened = 4 , family members = 3 / FH-Cincinnati-3, 5% to 15% LDLR Activity / Software predictions: Damaging

proposed classification - variant undergoing re-assessment, contact laboratory

The p.P526S pathogenic mutation (also known as c.1576C>T and p.P505S), located in coding exon 10 of the LDLR gene, results from a C to T substitution at nucleotide position 1576. The proline at codon 526 is replaced by serine, an amino acid with similar properties. This variant has been detected in individuals with familial hypercholesterolemia (FH); reduced LDL uptake was observed in assays performed on patient fibroblasts as well as in in vitro assays (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Day IN et al. Hum. Mutat., 1997;10:116-27; Nauck MS et al. Hum. Mutat., 2001 Aug;18:165-6; Maurer F et al. Swiss Med Wkly, 2016 Aug;146:w14326; Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855). Based on internal structural analysis, this variant is expected to be structurally disruptive (Rudenko G et al. Science. 2002 Dec;298(5602):2353-8; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Reported in several individuals with FH, some of which harbored an additional FH-related variant (Hobbs et al., 1992; Day et al., 1997; Nauck et al., 2001; Thormaehlen et al., 2015; Maurer et al., 2016); Also known as p.P505S and FH-Cincinnati-3; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25647241, 27497240, 1301956, 25487149, 9259195, 30586733, 31401775, 31447099, 11462246, 34037665, 31345425, 26582918, 35753512, 10357843, 10208479, 19837725)

The frequency of this variant in the general population, 0.000023 (3/128988 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with hypercholesterolemia (PMID: 9259195 (1997), 11462246 (2001), 27497240 (2016), 31345425 (2019), 34037665 (2021)). Functional studies have reported that this variant is damaging by causing LDLR activity to decrease to 5% to 15% of wildtype (PMID: 1301956 (1992)) that is likely due to an error in biosynthesis or turnover (PMID: 25647241 (2015)). 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 proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 526 of the LDLR protein (p.Pro526Ser). This variant is present in population databases (rs730882106, gnomAD 0.002%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 9259195, 11462246, 27497240; Invitae). This variant is also known as p.Pro505Ser. ClinVar contains an entry for this variant (Variation ID: 183120). 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%. Experimental studies have shown that this missense change affects LDLR function (PMID: 1301956, 25647241). For these reasons, this variant has been classified as Pathogenic.

This missense variant replaces proline with serine at codon 526 in the third LDLR type B repeat of the EGF precursor homology domain of the LDLR protein. This variant is also known as p.Pro505Ser in the mature protein; FH Cincinnati-3. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant interferes with protein transport and significantly affects LDLR biosynthesis or turnover (PMID: 25647241). Another functional study has shown significantly reduced LDLR activity (5-15% of the wild type) in cells from an individual with heterozygous hypercholesterolemia (PMID: 1301956). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 1301956, 9259195, 10208479, 11462246, 27497240, 31345425, 34037665; Color internal data). This variant has been identified in 3/282624 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

The LDLR c.1576C>T variant is predicted to result in the amino acid substitution p.Pro526Ser. This variant is alternatively referred to as p.Pro505Ser using legacy nomenclature, has been reported in several individuals with familial hypercholesterolemia (see for example, Hobbs et al. 1992. PubMed ID: 1301956; Table S2, Trinder et al. 2019. PubMed ID: 31345425; Table E4, Similuk et al. 2022. PubMed ID: 35753512). This variant has been reported in an individual with familial hypercholesterolemia who also carried an APOB p.Arg3527Gln variant (Maurer et al. 2016. PubMed ID: 27497240) and found in a control individual (Do et al. 2015. PubMed ID: 25487149). Functional studies suggest this variant results in decreased LDLR protein expression and impaired activity (Table S6, Thormaehlen et al. 2015. PubMed ID: 25647241; Maurer et al. 2016. PubMed ID: 27497240). This variant has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain significance to pathogenic (https://preview.ncbi.nlm.nih.gov/clinvar/variation/183120/). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.