ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.352G>T (p.Asp118Tyr) (rs730882080)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211613 SCV000294648 likely pathogenic 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 RCV000211613 SCV000503145 uncertain significance Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 , family member = 1 with co-segregation / FH-Naple-3 / Software predictions: Conflicting
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000454392 SCV000539518 likely pathogenic Homozygous familial hypercholesterolemia 2020-07-15 criteria provided, single submitter clinical testing The p.Asp118Tyr variant in LDLR has been identified in the heterozygous state in at least 6 individuals with hypercholesterolemia and segregated with disease in > 4 affected relatives with definite or probable familial hypercholesterolemia (FH) from at least 2 families (Bertolini 1999 PMID: 9974426, Bertolini 2000 PMID: 10978268, Liguori 2001 PMID: 11317362, Campagna 2008 PMID: 17196209, Romano 2010 PMID: 20045108, Bertolini 2013 PMID: 23375686, Scicali 2017 PMID: 28958694, Pirillo 2017 PMID: 28965616, Trinder 2019 PMID: 31345425). It has also been reported in 1 homozygote and 3 compound heterozygotes (with additional pathogenic LDLR variants) with hypercholesterolemia, at least 3 of whom had a more severe presentation (Bertolini 2000 PMID: 10978268, Liguori 2001 PMID: 11317362, Campagna 2008 PMID: 17196209, Bertolini 2013 PMID: 23375686). Additionally, this variant has been reported in 2 individuals with early myocardial infarction (Thormaehlen 2015 PMID: 25647241). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 183085) and has also been identified in 0.003% (3/111436) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies suggest that the variant has only a mild impact protein function (Bertolini 2013 PMID: 23375686, Thormaehlen 2015 PMID: 25647241). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. 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: PS4_Moderate, PM3, PP1, PM2_Supporting.
Color Health, Inc RCV001186038 SCV001352368 likely pathogenic Familial hypercholesterolemia 2019-07-27 criteria provided, single submitter clinical testing
Invitae RCV001186038 SCV001411750 uncertain significance Familial hypercholesterolemia 2019-01-17 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 118 of the LDLR protein (p.Asp118Tyr). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs730882080, ExAC 0.003%). This variant has been observed in several individuals affected with heterozygous or homozygous familial hypercholesterolemia or myocardial infarction (PMID: 9974426, 23375686, 28965616, 11317362, 25487149). This variant is also known as D97Y, FH-Napoli-3 or Naples-3 in the literature. ClinVar contains an entry for this variant (Variation ID: 183085). This variant has been reported to have conflicting or insufficient data to determine the effect on LDLR protein function (PMID: 25647241). 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.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000211613 SCV001432648 likely pathogenic Familial hypercholesterolemia 1 2019-05-10 criteria provided, single submitter research
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II RCV000211613 SCV001653588 likely pathogenic Familial hypercholesterolemia 1 2021-05-24 criteria provided, single submitter clinical testing
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161954 SCV000189529 not provided not provided no assertion provided in vitro
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211613 SCV000268559 pathogenic Familial hypercholesterolemia 1 2015-09-03 no assertion criteria provided clinical testing

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