ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.268G>A (p.Asp90Asn) (rs749038326)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000238573 SCV000599321 likely pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter curation
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000238573 SCV000503122 likely benign Familial hypercholesterolemia 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 , family members = 2 with co-segregation / other mutations at same codon / Software predictions: Damaging
Color RCV000776467 SCV000912016 likely pathogenic Familial hypercholesterolemias 2018-04-26 criteria provided, single submitter clinical testing Likely Pathogenic variant based on current evidence: This variant (also known as p.Asp69Asn in the mature protein) is a missense variant located in the second LDLR type A of the ligand binding domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. An experimental study has shown that the mutant protein is trapped in the endoplasmic reticulum and shows weak cell surface expression (PMID: 12837857). Cells from an individual compound heterozygous for this variant and p.Cys222* showed no detectable LDLR activity (PMID: 16343504). It has been reported in multiple European and Chinese individuals diagnosed with familial hypercholesterolemia (PMID: 9259195, 9763532, 12436241, 12837857, 15823276, 16250003, 16343504). This variant has been identified in 17/277232 chromosomes (16/18868 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence this variant is classified as Likely Pathogenic.
GeneDx RCV000494304 SCV000582689 pathogenic not provided 2017-05-03 criteria provided, single submitter clinical testing The D90N variant in the LDLR gene has been reported previously in association with familial hypercholesterolemia (for examples, see Chang et al., 2003; Norsworthy et al., 2014; Xiang et al., 2017). Functional studies show D90N decreases LDLR on the cell surface and decreases LDL binding and internalization (Chang et al., 2003). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D90N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and is located in the LDL-receptor class A 2 domain (Uniprot). Missense variants at the same residue (D90Y, D90G, D90A, c.270T>A and c.270T>G D90E) have been reported in association with familial hypercholesterolemia, supporting the functional importance of this region of the protein (Hobbs et al., 1992; Rubinsztein et al., 1993; Marduel et al., 2010; Kolansky et al., 2008; Gabcova et al., 2016). Based on the ACMG recommendations, D90N is interpreted as a known pathogenic sequence change.
Invitae RCV000238573 SCV000816377 pathogenic Familial hypercholesterolemia 2018-06-15 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 90 of the LDLR protein (p.Asp90Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs749038326, ExAC 0.07%). This variant has been reported in many individuals affected with familial hypercholesterolemia (PMID: 23375686, 16343504, 27206935, 25962062, 21376320, 12436241, 27765764, 15823276, 9763532, 12837857, 9259195, 22390909). This variant is also known as p.Asp69Asn in the literature. ClinVar contains an entry for this variant (Variation ID: 251105). Experimental studies have shown that this missense change affects LDLR subcellular localization and reduces LDLR activity (PMID: 12837857). Several different missense substitutions at this codon (p.Asp90Gly, p.Asp90Ala, p.Asp90Tyr) have been reported in individuals with familial hypercholesterolemia (PMID: 1301956, 19026292, 8347689). This suggests that the aspartic acid residue is critical for LDLR protein function and that other missense substitutions at this position may also be pathogenic. 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 RCV000238573 SCV000294569 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000238573 SCV000606056 pathogenic Familial hypercholesterolemia no assertion criteria provided research
Robarts Research Institute,Western University RCV000238573 SCV000484708 likely pathogenic Familial hypercholesterolemia criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000238573 SCV000583645 pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing

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