Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000238573 | SCV000294569 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Robarts Research Institute, |
RCV000238573 | SCV000484708 | likely pathogenic | Familial hypercholesterolemia 1 | criteria provided, single submitter | clinical testing | ||
Centre de Génétique Moléculaire et Chromosomique, |
RCV000238573 | SCV000503122 | likely benign | Familial hypercholesterolemia 1 | 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 |
Gene |
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. |
U4M - |
RCV000238573 | SCV000583645 | pathogenic | Familial hypercholesterolemia 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
Cardiovascular Research Group, |
RCV000238573 | SCV000599321 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | curation | |
Invitae | RCV000776467 | SCV000816377 | pathogenic | Familial hypercholesterolemia | 2019-12-11 | 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. For these reasons, this variant has been classified as Pathogenic. |
Color | RCV000776467 | SCV000912016 | likely pathogenic | Familial hypercholesterolemia | 2019-11-15 | criteria provided, single submitter | clinical testing | |
Brunham Lab, |
RCV000238573 | SCV001432642 | pathogenic | Familial hypercholesterolemia 1 | 2019-01-15 | criteria provided, single submitter | research | |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000238573 | SCV000606056 | pathogenic | Familial hypercholesterolemia 1 | no assertion criteria provided | research |