ClinVar Genomic variation as it relates to human health

subject mutated among 2600 FH index cases screened = 1/Software predictions: Conflicting

This missense variant (also known as p.Pro805Thr in the mature protein) replaces proline with threonine at codon 826 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). This variant changes a highly conserved proline residue from the Asn-Pro-Val-Tyr motif in the cytoplasmic domain that interacts with the clathrin adaptor protein LDLRAP1 and is required for coated pit-mediated internalization of LDLR (PMID: 1968060, 22509010). Although functional studies have not been performed for this variant, a different amino acid substitution at this position (Pro to Ala) has been shown to significantly reduce LDL internalization to 25% of wild type activity, while having no impact on LDL binding to LDLR at the cell surface (PMID: 1968060). This study demonstrates a critical role of proline residue at codon 826 in LDLR function. This variant has been reported in individuals affected with familial hypercholesterolemia (dissertation by D’Agostino 2014, PMID: 23669246). This variant has not been identified 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.2476C>A; p.Pro826Thr variant (rs879255217) is reported in the literature in individuals affected with familial hypercholesterolemia, in either the heterozygous or compound heterozygous state (Bertolini 2020, Di Taranto 2020, Futema 2013). This variant is also reported in ClinVar (Variation ID: 252343), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism.. The proline at codon 826 is highly conserved and computational analyses predict that this variant is deleterious (REVEL: 0.883). Based on available information, this variant is considered to be likely pathogenic. References: Bertolini S et al. Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features. Atherosclerosis. 2020 Nov;312:72-78. PMID: 32977124. Di Taranto MD et al. A Real-World Experience of Clinical, Biochemical and Genetic Assessment of Patients with Homozygous Familial Hypercholesterolemia. J Clin Med. 2020 Jan 14;9(1):219. PMID: 31947532. Futema M et al. Analysis of the frequency and spectrum of mutations recognised to cause familial hypercholesterolaemia in routine clinical practice in a UK specialist hospital lipid clinic. Atherosclerosis. 2013 Jul;229(1):161-8. PMID: 23669246.

The p.P826T variant (also known as c.2476C>A), located in coding exon 17 of the LDLR gene, results from a C to A substitution at nucleotide position 2476. The proline at codon 826 is replaced by threonine, an amino acid with highly similar properties. This variant has been reported in an individual from a familial hypercholesterolemia (FH) cohort (Futema M et al. Atherosclerosis, 2013 Jul;229:161-8), and co-occurred with a pathogenic mutation in the LDLR gene in siblings reported to have homozygous FH presentation; however, details were limited (Di Taranto MD et al. J Clin Med. 2020 Jan;9(1)). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Internal structural analysis suggests that this variant, which impacts the NPXY motif required for receptor internalization, will disrupt protein function (Chen WJ et al. J Biol Chem. 1990;265(6):3116-23; Ambry internal data). 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.