ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2441G>A (p.Arg814Gln)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237126 SCV000296010 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 RCV000237126 SCV000503489 likely benign Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 3 , family member = 1/previously described in association with FH/Software predictions: Conflicting
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237126 SCV000583953 likely pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000237126 SCV000588667 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001420704 SCV000697230 likely benign not specified 2021-04-26 criteria provided, single submitter clinical testing Variant summary: LDLR c.2441G>A (p.Arg814Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 251604 control chromosomes, predominantly at a frequency of 0.0035 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3.5- fold the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Early Onset Coronary Artery Disease phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.2441G>A has been reported in the literature in individuals affected with hypercholesterolemia without strong evidence for causality (e.g. Arca_1997, Thiart_2000, Vergotine_2001, Humphries_2006, Sanchez-Hernandez_2016, Futema_2021). These reports do not provide unequivocal conclusions about association of the variant with Early Onset Coronary Artery Disease. One publication reports a modest reduction of LDL-R activity in-vivo in a patient with the variant (e.g. Arca_1997). Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=4; uncertain significance, n=1; likely pathogenic, n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000776249 SCV000752439 likely benign Familial hypercholesterolemia 2020-11-22 criteria provided, single submitter clinical testing
Color Health, Inc RCV000776249 SCV000911501 likely benign Familial hypercholesterolemia 2020-01-23 criteria provided, single submitter clinical testing
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000162024 SCV000189627 not provided not provided no assertion provided in vitro
CSER _CC_NCGL, University of Washington RCV000148584 SCV000190298 uncertain significance Hypercholesterolaemia 2014-06-01 no assertion criteria provided research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237126 SCV000606653 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000162024 SCV001553978 uncertain significance not provided no assertion criteria provided clinical testing The LDLR p.Arg646Gln variant was identified in 4 of 1430 proband chromosomes (frequency: 0.0028) from individuals or families with familial hypercholesterolemia (FH) or high LDL-C (Humphries_2006_PMID:16389549; Thiart_2000_PMID:10882754; Santos_2014_PMID:24529145; Lange_2014_PMID:24507775). The variant was also identified in dbSNP (ID: rs5928), LOVD 3.0 and ClinVar (classified as likely benign by 4 submitters, as a VUS by 3 submitters, as likely pathogenic by 1 submitter and as pathogenic by 1 submitter). The variant was identified in control databases in 101 of 282836 chromosomes at a frequency of 0.000357 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 93 of 24970 chromosomes (freq: 0.003724), Other in 1 of 7224 chromosomes (freq: 0.000138), Latino in 4 of 35440 chromosomes (freq: 0.000113), South Asian in 1 of 30614 chromosomes (freq: 0.000033) and European (non-Finnish) in 2 of 129174 chromosomes (freq: 0.000015), while the variant was not observed in the Ashkenazi Jewish, East Asian or European (Finnish) populations. The p.Arg646 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. 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. 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.

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