Submissions for variant NM_000527.5(LDLR):c.796G>A (p.Asp266Asn) (rs875989907)

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211615	SCV000294976	likely pathogenic	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000211615	SCV000503237	likely pathogenic	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 / previously described in association with FH / Software predictions: Damaging
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation	RCV000211615	SCV000540758	likely pathogenic	Familial hypercholesterolemia 1	2016-11-05	criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000211615	SCV000583740	pathogenic	Familial hypercholesterolemia 1	2017-03-30	criteria provided, single submitter	clinical testing
Fundacion Hipercolesterolemia Familiar	RCV000211615	SCV000607501	pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000211615	SCV000839983	likely pathogenic	Familial hypercholesterolemia 1	2017-09-19	criteria provided, single submitter	clinical testing	This c.796G>A (p.Asp266Asn) variant in the LDLR gene has been reported in multiple patients with familial hypercholesterolemia (PMID: 11810272, 23375686). Multiple different amino acid substitutions affecting aspartic acid at position 266 of the LDLR protein have also been reported in patients with familial hypercholesterolemia (PMID: 1301956, 12417285, 28235710). The c.796G>A variant is extremely rare in the general population and aspartic acid at position 266 of the LDLR protein is highly evolutionarily conserved. The c.796G>A (p.Asp266Asn) variant in the LDLR gene is classified as likely pathogenic.
Invitae	RCV001037156	SCV001200555	pathogenic	Familial hypercholesterolemia	2019-04-25	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with asparagine at codon 266 of the LDLR protein (p.Asp266Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with hypercholesterolemia (PMID: 23375686, 14974088, 22417841, 22698793). This variant is also known as p.Asp245Asn in the literature. ClinVar contains an entry for this variant (Variation ID: 226334). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). This variant disrupts the p.Asp266 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 23375686, 21310417, 20663204, 22698793, 26238499, 11196104). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211615	SCV000268585	pathogenic	Familial hypercholesterolemia 1	2013-02-26	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000211615	SCV000606225	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research
Broad Institute Rare Disease Group, Broad Institute	RCV000211615	SCV001422934	likely pathogenic	Familial hypercholesterolemia 1	2020-01-22	no assertion criteria provided	curation	The p.Asp266Asn (sometimes called p.Asp245Asn) variant in LDLR has been reported in at least 15 individuals (including 8 Norwegian, 3 Tunisian, 1 Dutch, 1 Japanese, and 1 German individuals) with Hypercholesterolemia, segregated with disease in 11 affected relatives from 3 families (PMID: 12414836, 11810272, 15199436, 12417285, 19446849, 14974088), and has been identified in 0.006533% (2/30616) of South Asian chromosomes and 0.005437% (1/18394) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs875989907). 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 likely pathogenic and pathogenic in ClinVar (Variation ID: 226334). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional variant with a different amino acid change at the same position (p.Asp266Glu) has been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 161287). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM5_supporting, PS4_Moderate, PP1_Moderate, PP3 (Richards 2015).