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

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238033	SCV002506397	benign	Hypercholesterolemia, familial, 1	2021-12-13	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1024G>A (p.Asp342Asn) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1 and BP4) 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: BA1 - FAF = 0.005579 (0.56%) in African exomes (gnomAD v2.1.1). It is above 0.5%, so BA1 is met. BP4 - REVEL = 0.283. it is below 0.50, splicing evaluation required. Functional data on splicing not available. A) not on limits B) variant is exonic and at least 50bp downstream from canonical acceptor site but it does not create GT. Variant is not predicted to alter splicing, so BP4 is met.
Laboratory for Molecular Medicine, Mass General Brigham 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, http://exac.broadinstitute.org). 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	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	RCV000238033	SCV000503281	benign	Hypercholesterolemia, familial, 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
Invitae	RCV000771314	SCV000627010	benign	Familial hypercholesterolemia	2024-01-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771314	SCV000903570	likely benign	Familial hypercholesterolemia	2018-03-11	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000238033	SCV001285933	likely benign	Hypercholesterolemia, familial, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000218676	SCV001431979	benign	not specified	2021-11-29	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 0.00061 in 292610 control chromosomes, predominantly at a frequency of 0.0064 within the African or African-American subpopulation in the gnomAD database, including 3 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 with hypercholesterolemia, however it was also found in healthy controls (e.g. Do_2015). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated normal activities for this variant (Guo_2019). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and reported the variant with conflicting assessments (i.e. VUS (n=3), likely benign (n=3) / benign (n=2)). Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV002381456	SCV002690895	likely benign	Cardiovascular phenotype	2017-10-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000162022	SCV000189625	not provided	not provided		no assertion provided	in vitro
CSER _CC_NCGL, University of Washington	RCV002051667	SCV000190294	uncertain significance	Hypercholesterolemia	2014-06-01	flagged submission	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	flagged submission	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 of Genetics and Molecular Cardiology, University of São Paulo	RCV000238033	SCV000588540	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	flagged submission	research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238033	SCV000606294	pathogenic	Hypercholesterolemia, familial, 1		flagged submission	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000162022	SCV001552212	uncertain significance	not provided		flagged submission	clinical testing	The LDLR p.Asp301Asn variant was identified in dbSNP (ID: rs139361635) and in ClinVar (classified benign 2 times, likely benign 2 times, a VUS 4 times and pathogenic once). The variant was also identified in control databases in 168 of 282430 chromosomes (3 homozygous) at a frequency of 0.000595 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 160 of 24944 chromosomes (freq: 0.006414), Latino in 6 of 35432 chromosomes (freq: 0.000169), Other in 1 of 7220 chromosomes (freq: 0.000139) and European (non-Finnish) in 1 of 128970 chromosomes (freq: 0.000008), but not in the Ashkenazi Jewish, East Asian, European (Finnish) or South Asian populations. The D301N variant in LDLR has been reported in 4 individuals with possible or definitive hypercholesterolemia (Do_1997_PMID:25487149; Fouchier_2001_PMID:11810272; Sjouke_2015_PMID:24585268; Leigh_2008_PMID:18325082). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Asp301 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.