ClinVar Genomic variation as it relates to human health

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 263 of the LDLR protein (p.Asp263Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 24507775, 28965616, 34297352; Invitae). ClinVar contains an entry for this variant (Variation ID: 960398). 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%. For these reasons, this variant has been classified as Pathogenic.

This missense variant replaces aspartic acid with glycine at codon 263 in the LDLR type A repeat 6 of the LDLR protein. This variant is also known as p.Asp242Gly in the mature protein. 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). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in multiple heterozygous individuals affected with familial hypercholesterolemia (PMID: 24507775, 28958694, 28965616, 34297352; ClinVar SCV002675592.1, SCV001653609.1). This variant has also been observed in homozygous state in an individual affected with severe familial hypercholesterolemia, as well as in multiple heterozygous first-degree relatives affected with familial hypercholesterolemia (DOI:10.1016/j.atherosclerosis.2019.06.630). 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.

This missense variant (also known as p.Asp242Gly in the mature protein) replaces aspartic acid with glycine at codon 263 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 observed in multiple heterozygous individuals affected with familial hypercholesterolemia (PMID: 24507775, 28958694, 28965616, 34297352; ClinVar SCV002675592.1). This variant has been observed in a homozygous individual affected with severe familial hypercholesterolemia, as well as in her multiple, heterozygous, first-degree relatives affected with familial hypercholesterolemia (Turner et al, 2019, https://doi.org/10.1016/j.atherosclerosis.2019.06.630). 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 p.D263G variant (also known as c.788A>G), located in coding exon 5 of the LDLR gene, results from an A to G substitution at nucleotide position 788. The aspartic acid at codon 263 is replaced by glycine, an amino acid with similar properties. This variant has been identified in multiple individuals with familial hypercholesterolemia (FH) (Lange LA et al. Am J Hum Genet, 2014 Feb;94:233-45; Pirillo A et al. Atheroscler Suppl, 2017 Oct;29:17-24; Scicali R et al. Nutr Metab Cardiovasc Dis, 2018 01;28:35-43; Ambry internal data). Based on internal structural analysis, this variant is deleterious, impacting a residue in the conserved cluster of acidic amino acids at the C-terminal end of LDLR class A repeat 6 (Jeon H and Blacklow C. Annu. Rev. Biochem. 2005;74:535-62; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.788A>G (p.Asp263Gly) variant has been reported in at least six unrelated individuals affected with familial hypercholesterolemia and is reported to segregate with disease in seven individuals in two families (Di Taranto MD et al., PMID: 34297352; Lange LA et al., PMID: 24507775; Pirillo A et al., PMID: 28965616; Scicali R et al., PMID: 28958694; Turner T et al., doi: https://doi.org/10.1016/j.atherosclerosis .2019.06.630). This variant has been reported in the ClinVar database as a germline pathogenic or likely pathogenic variant by four submitters. Another variant in the same codon, c.787G>T (p.Asp263Tyr), has been reported as likely pathogenic (ClinVar Variation ID: 2719688). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to LDLR function. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic.