Submissions for variant NM_000527.5(LDLR):c.268G>A (p.Asp90Asn) (rs749038326)

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238573	SCV000294569	likely pathogenic	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute,Western University	RCV000238573	SCV000484708	likely pathogenic	Familial hypercholesterolemia 1		criteria provided, single submitter	clinical testing
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 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
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.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000238573	SCV000583645	pathogenic	Familial hypercholesterolemia 1	2017-03-30	criteria provided, single submitter	clinical testing
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge	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, Centre for Heart and Lung Innovation,University of British Columbia	RCV000238573	SCV001432642	pathogenic	Familial hypercholesterolemia 1	2019-01-15	criteria provided, single submitter	research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000238573	SCV000606056	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research