ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1690A>C (p.Asn564His) (rs397509365)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211626 SCV000268628 pathogenic Familial hypercholesterolemia 2012-08-01 no assertion criteria provided clinical testing
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000211626 SCV000322969 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research 0/208 non-FH alleles; 0/100 control subjects
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000211626 SCV000503384 likely pathogenic Familial hypercholesterolemia 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 8 , family member = 1 with co-segregation / systematically associated with c.2397_2405del, p.Val800_Leu802del & other mutations at same codon / Software predictions: Damaging
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000211626 SCV000733825 pathogenic Familial hypercholesterolemia no assertion criteria provided clinical testing
Fundacion Hipercolesterolemia Familiar RCV000211626 SCV000607623 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Iberoamerican FH Network RCV000211626 SCV000748058 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Invitae RCV000211626 SCV000820242 uncertain significance Familial hypercholesterolemia 2018-04-04 criteria provided, single submitter clinical testing This sequence change replaces asparagine with histidine at codon 564 of the LDLR protein (p.Asn564His). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with hypercholesterolemia (PMID: 7550239, 17765246, 23054246) including many in whom it has been shown to coincide on the same chromosome (in cis) with p.Val800_Leu802del (PMID: 9147888, 9143924, 12442279, 10090484). However, presence of p.Val800_Leu802del can not be excluded from the individuals for whom only this single c.1690A>C variant was reported. This variant is also known as N543H in the literature. ClinVar contains entries for this variant (Variation ID: 3737, 226365). Experimental studies have shown that this variant has a mild impact on LDLR protein function. However, when expressed with p.Val800_Leu802del in the same cDNA, LDLR receptor function was greatly reduced (PMID: 9143924). A different missense substitution at this codon (p.Asn564Ser) has been determined to be pathogenic (PMID: 9654205, 21376320 20145306, 20538126). This suggests that the asparagine residue is critical for LDLR protein function and that other missense substitutions at this position may also be pathogenic. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
LDLR-LOVD, British Heart Foundation RCV000211626 SCV000295581 uncertain significance Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211626 SCV000606484 pathogenic Familial hypercholesterolemia no assertion criteria provided research
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000211626 SCV000588602 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Robarts Research Institute,Western University RCV000211626 SCV000484725 likely pathogenic Familial hypercholesterolemia criteria provided, single submitter clinical testing

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