ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.337G>A (p.Glu113Lys) (rs769383881)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000791453 SCV000285029 likely pathogenic Familial hypercholesterolemia 2020-10-25 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 113 of the LDLR protein (p.Glu113Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs769383881, ExAC <0.01%). This variant has been reported to segregate with elevated LDL levels in a single family (PMID: 10807540). It has also been reported in several unrelated individuals affected with hypercholesterolemia (PMID: 16250003, 17539906, Invitae). This variant is also known as E92K in the literature. ClinVar contains an entry for this variant (Variation ID: 237872). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). 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.
LDLR-LOVD, British Heart Foundation RCV000232879 SCV000294636 uncertain significance Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Fundacion Hipercolesterolemia Familiar RCV000232879 SCV000607448 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Color Health, Inc RCV000791453 SCV001353456 likely pathogenic Familial hypercholesterolemia 2020-03-10 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV001195308 SCV001365633 likely pathogenic Homozygous familial hypercholesterolemia 2020-11-17 criteria provided, single submitter clinical testing 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284647 SCV001470537 likely pathogenic not provided 2019-12-18 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one patient with expected phenotype for this gene. Statistically associated with disease in a single family.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287502 SCV001474197 likely pathogenic none provided 2020-04-17 criteria provided, single submitter clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000232879 SCV000606089 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Broad Institute Rare Disease Group, Broad Institute RCV000791453 SCV001422705 uncertain significance Familial hypercholesterolemia 2020-01-22 no assertion criteria provided curation 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).

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