ClinVar Genomic variation as it relates to human health

Variant summary: LDLR c.337G>A (p.Glu113Lys) results in a conservative amino acid change located in an LDL-receptor class A repeat (IPR002172) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250568 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.337G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g., Wu_2000, Fouchier_2005, Taylor_2007, Trinder_2020, Marco-Benedi_2022, Sturm_2021), and the variant was also shown to segregate with disease in at least one family (e.g., Wu_2000). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16250003, 34456049, 34037665, 17539906, 33079599, 10807540). Multiple submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting interpretations (pathogenic, n = 3; likely pathogenic, n = 11; VUS, n = 3). Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 113 of the LDLR protein (p.Glu113Lys). This variant is present in population databases (rs769383881, gnomAD 0.01%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 10807540). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 237872). 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 (also known as p.Glu92Lys in the mature protein) replaces glutamic acid with lysine at codon 113 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypercholesterolemia (PMID: 16250003, 17539906). It has been shown that this variant segregates with disease in 1 family (PMID: 10807540). This variant has been identified in 8/281964 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

The p.Glu113Lys variant in LDLR has been reported in at least 2 individuals with hypercholesterolemia, 1 individual with probable hypercholesterolemia, and segregated with disease in 7 affected relatives from 1 family (Wu 2000 PMID: 10807540, Fouchier 2005 PMID: 16250003, Taylor 2007 PMID: 17539906). It has also been identified in 0.002% (3/128566) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported by other clinical laboratories in ClinVar (Variation ID: 237872). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant familial hypercholesterolemia (FH). ACMG/AMP Criteria applied: PP1_Strong, PM2_Supporting, PS4_Supporting.

The p.Glu113Lys variant in LDLR has been reported in10 individuals with familial hypercholesterolemia, segregated with disease in 8 affected relatives from 1 family (PMID: 16250003, 17539906, 10807540), and has been identified in 0.01% (3/30614) of South Asian chromosomes, 0.006% (2/35432) Latino chromosomes, and 0.002% (3/128566) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs769383881). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as a VUS, likely pathogenic, and pathogenic (Variation ID#: 237872). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Glu113Lys variant is uncertain. ACMG/AMP Criteria applied: PP1_strong, BP4, PS4_supporting (Richards 2015).

The frequency of this variant in the general population, 0.000098 (3/30614 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with possible familial hypercholesterolemia (PMIDs: 34037665 (2021), 17539906 (2007)), heterozygous FH (heFH) (PMID: 34456049 (2022)), and autosomal dominant hypercholesterolemia (ADH) (PMID: 16250003 (2005)). This variant was also reported in a family with several individuals affected by hyperlipoproteinemia and to co-segregate with high low density lipoprotein (LDL) levels (PMID: 10807540 (2000)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, this variant is classified as likely pathogenic.

This missense variant (also known as p.Glu92Lys in the mature protein) replaces glutamic acid with lysine at codon 113 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypercholesterolemia (PMID: 16250003, 17539906). It has been shown that this variant segregates with disease in 1 family (PMID: 10807540). This variant has been identified in 8/281964 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

The p.E113K variant (also known as c.337G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 337. The glutamic acid at codon 113 is replaced by lysine, an amino acid with similar properties. This alteration was reported to segregate with elevated LDL-C levels in one family (Wu LL et al. J. Hum. Genet., 2000;45:154-8). In addition, this alteration has been reported in familial hypercholesterolemia (FH) cohorts (Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Taylor A et al. Clin. Genet., 2007 Jun;71:561-8). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Identified in patients with familial hypercholesterolemia referred for genetic testing at GeneDx and in published literature (PMID: 16250003, 17539906, 34037665, 34456049, 36299643); 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; Also known as p.(E92K); This variant is associated with the following publications: (PMID: 17539906, 37589137, 34037665, 34456049, 36299643, 30583242, 34906454, 16250003, 10807540)

LDLR: PP1:Strong, PM1, PM2, PS4:Moderate