ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1024G>A (p.Asp342Asn)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER _CC_NCGL, University of Washington RCV000148580 SCV000190294 uncertain significance Hypercholesterolaemia 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
GeneDx RCV000162022 SCV000234648 uncertain significance not provided 2016-02-04 criteria provided, single submitter clinical testing The D342N variant in the LDLR gene has been reported previously as a pathogenic variant in association with familial hypercholesterolemia, using alternate nomenclature D321N (Day et al., 1997; Fouchier et al., 2001). While 342N was identified in four patients with early-onset myocardial infarction, it was also identified in 10 control individuals of advanced age with no history of myocardial infarction. Additionally, cholesterol and LDL levels were not reported (Do et al., 2015). The NHLBI ESP Exome Sequencing Project reports that D342N was observed in 27/4406 (0.61%) alleles from individuals of African American background, indicating it may be a rare variant in this population. The D342N 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 not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function. In addition, in vitro overexpression and complementation experiments suggest that D342N is non-disruptive to LDLR activity (Thormaehlen et al., 2015). A research group recently concluded that there was no definitive evidence for a genotype/phenotype association of D342N with familial hypercholesterolemia (Amendola et al., 2015; Olfson et al., 2015). We interpret D342N as a variant of uncertain significance.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000218676 SCV000271916 uncertain significance not specified 2016-01-19 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Asp342Asn var iant in LDLR has been reported in 3 individuals with possible or definitive hype rcholesterolemia (Do 1997, Fouchier 2001, Sjouke 2015), including in one individ ual with a second LDLR variant. However, this variant has also been identified i n 0.6% (160/24944) of African chromosomes by the Genome Aggregation Consortium ( gnomAD, Computational prediction tools and cons ervation analysis suggest that the variant may not impact the protein, though th is information is not predictive enough to rule out pathogenicity. In summary, w hile the clinical significance of the p.Asp342Asn variant is uncertain, its freq uency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: P S4_Supporting, BS1, BP4.
LDLR-LOVD, British Heart Foundation RCV000238033 SCV000295146 likely benign 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 RCV000238033 SCV000503281 benign Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 / previously described in association with FH (linked to ethnicity ?) / Software predictions: Benign
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000238033 SCV000588540 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Invitae RCV000771314 SCV000627010 benign Familial hypercholesterolemia 2019-12-31 criteria provided, single submitter clinical testing
Color RCV000771314 SCV000903570 likely benign Familial hypercholesterolemia 2018-03-11 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000238033 SCV001285933 likely benign Familial hypercholesterolemia 1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Integrated Genetics/Laboratory Corporation of America RCV000218676 SCV001431979 likely benign not specified 2020-08-31 criteria provided, single submitter clinical testing Variant summary: LDLR c.1024G>A (p.Asp342Asn) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 261218 control chromosomes, predominantly at a frequency of 0.0066 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1024G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia (example: Day_1997). These reports however, do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. In functional assays, the variant showed normal activities (Guo_2019). Eight ClinVar submitters (evaluation after 2014) cite the variant as likely benign/benign (n=5) or uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000162022 SCV000189625 not provided not provided no assertion provided in vitro
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000238033 SCV000606294 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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