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

gnomAD frequency: 0.00001  dbSNP: rs875989907

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000211615	SCV002568103	pathogenic	Hypercholesterolemia, familial, 1	2022-05-04	reviewed by expert panel	curation	The NM_000527.5(LDLR):c. c.796G>A (p.Asp266Asn) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4, PM2, PM5_Strong, PS3_Moderate, PP1, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PS4 - Variant meets PM2. Variant identified in 10 unrelated index cases (1 case fulfilling Simon-Broome criteria published in PMID: 12414836; 1 case probably fulfilling Simon-Broome criteria published in PMID: 12417285; 1 case with DLCN criteria from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 4 cases with Simon-Broome criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 3 cases with DLCN criteria from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory); PM2 - PopMax MAF = 0.00006533 (0.006533%) in South Asian exomes (gnomAD v2.1.1); PM5_Strong - 4 other missense variants in the same codon: - NM_000527.5(LDLR): c.796G>T (p.Asp266Tyr) (ClinVar ID 251456) - Pathogenic by these guidelines. - NM_000527.5(LDLR): c.797A>T (p.Asp266Val) (ClinVar ID 251458) - Likely Pathogenic by these guidelines. - NM_001195803.2(LDLR):c.797A>G (p.Asp266Gly) (ClinVar ID 251457) - Likely pathogenic by these guidelines. - NM_001195803.2(LDLR): c.798T>A (p.Asp266Glu) - (ClinVar ID 161287) - Pathogenic by these guidelines. There are 2 variants in the same codon classified as Pathogenic by these guidelines. PS3_Moderate - Level 2 assay: PMID 12414836: Homozygous patient cells, 125I assays - result - <2% LDL-LDLR binding and internalisation. Functional study is consistent with damaging effect; PP1 - 3 informative meioses identified by Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); PP3 - REVEL = 0,83; PP4 - Variant meets PM2. Identified in at least 1 FH case fulfilling Simon-Broome criteria published in PMID 12414836.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211615	SCV000268585	pathogenic	Hypercholesterolemia, familial, 1	2022-01-05	criteria provided, single submitter	clinical testing	The LDLR p.Asp266Asn (originally p.Asp245Asn) missense variant occurs within the ligand-binding domain of the LDL-receptor and is pathogenic for familial hypercholesterolaemia (FH). In silico algorithms (PolyPhen2, SIFT, MutationTaster) predict LDLR p.Asp266Asn to be pathogenic. It, along with different missense variants at the same codon (p.Asp266Glu, p.Asp266Gly, p.Asp266Tyr, p.Asp266Val), has previously been identified in multiple cohorts of FH patients worldwide. Studies in cultured patient cells showed that LDL-receptor activity in the homozygous state is <2% of normal (PMID:12414836).
LDLR-LOVD, British Heart Foundation	RCV000211615	SCV000294976	likely pathogenic	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000211615	SCV000583740	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Fundacion Hipercolesterolemia Familiar	RCV000211615	SCV000607501	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000211615	SCV000839983	likely pathogenic	Hypercholesterolemia, familial, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001037156	SCV001200555	pathogenic	Familial hypercholesterolemia	2023-04-26	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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, 11196104, 20663204, 21310417, 22698793, 23375686, 26238499). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. ClinVar contains an entry for this variant (Variation ID: 226334). This variant is also known as p.Asp245Asn. This missense change has been observed in individuals with hypercholesterolemia (PMID: 14974088, 22417841, 22698793, 23375686). This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 266 of the LDLR protein (p.Asp266Asn).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000211615	SCV001422934	likely pathogenic	Hypercholesterolemia, familial, 1	2020-01-22	criteria provided, single submitter	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).
GeneDx	RCV002255136	SCV002526553	pathogenic	not provided	2022-09-12	criteria provided, single submitter	clinical testing	Disrupts a negatively charged triplet, Ser-Asp-Glu, located at the carboxyl-terminal end of the LDL- receptor class A6 repeat domain that is critical for ligand binding (Schneider et al., 2003); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as FH-Tozeur and p.(D245N); This variant is associated with the following publications: (PMID: 34037665, 30241732, 32331935, 12827279, 23375686, 31447099, 31491741, 33740630, 11810272, 32977124, 12414836, 31386798, 15199436, 14974088, 19446849, 21310417, 22698793, 15823288, 22417841, 26582918, 12417285)
Revvity Omics, Revvity	RCV000211615	SCV003829653	likely pathogenic	Hypercholesterolemia, familial, 1	2021-12-15	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017503	SCV004847729	likely pathogenic	Homozygous familial hypercholesterolemia	2019-04-16	criteria provided, single submitter	clinical testing	The p.Asp266Asn variant in LDLR has been reported in the heterozygous state in 3 individuals with familial hypercholesterolemia (FH), in the homozygous state in 1 individual with a more severe presentation and segregated with disease in 2 affected individuals from 2 families (Fouchier 2001, Slimani 2012, Tichy 2012, Bertolini 2013). It has also been reported by other clinical laboratories in ClinVar (Variation ID 161287) and has identified in 3/251478 pan-ethnic chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of FH in the general population. Computational prediction tools and conservation analysis suggest that this variant may impact the protein. In addition, another variant involving this codon (p.Asp266Glu) has been identified in individuals with FH and is classified as pathogenic by this laboratory. 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 FH. ACMG/AMP criteria applied: PM2, PM5, PP3, PS4_Supporting.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001037156	SCV005045762	pathogenic	Familial hypercholesterolemia	2023-08-28	criteria provided, single submitter	clinical testing	The c.796G>A (p.Asp266Asn) variant (also known as p.Asp245Asn) in the LDLR gene that encodes for low density lipoprotein receptor, has been identified in multiple unrelated individuals (>10) who fulfill the clinical criteria of familial hypercholesterolemia and segregated with disease in multiple families (PMID:11810272, 23375686, 15199436, 12417285, 19446849, 14974088). Experimental studies using homozygous patient derived cells revealed less than 2% LDLR activity compared to wild type (PMID: 12414836). In-silico computational prediction tools suggest that the p.Asp266Asn variant may have deleterious effect on the protein function (REVEL score: 0.832). This variant is rare (3/251478; 0.00001193) in the general population database, gnomAD. This variant is classified as pathogenic by multiple submitters in the ClinVar database including the ClinGen Variant Curation Expert Panel (ClinVar ID: 226334). Other missense variants affecting the same amino acid, p.Asp266Glu and p.Asp266Tyr, are classified as pathogenic by multiple ClinVar submitters including the ClinGen Variant Curation Expert Panel (ClinVar ID: 251456, 161287). Therefore, the c.796G>A (p.Asp266Asn) variant in the LDLR gene is classified as pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211615	SCV000606225	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research