ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1783C>T (p.Arg595Trp) (rs373371572)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000518174 SCV000614004 likely pathogenic not provided 2017-06-16 criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148597 SCV000190312 uncertain significance Hypercholesterolaemia 2014-06-01 no assertion criteria provided research
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000237585 SCV000503414 likely pathogenic Familial hypercholesterolemia 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 / previously described in association with FH/software prediction damaging
Color RCV000588105 SCV000909180 likely pathogenic Familial hypercholesterolemias 2018-08-11 criteria provided, single submitter clinical testing Likely Pathogenic variant based on current evidence: This missense variant (also known as p.Arg574Trp in the mature protein) is located in the fifth LDLR type B repeat of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. While this variant is rare in the general population (2/277214 chromosomes in the Genome Aggregation Database (gnomAD)), it has been reported in over 10 unrelated individuals diagnosed with familial hypercholesterolemia (PMID: 11737238, 16250003, 20538126, 25461735, 27784735, 28502510). Based on available evidence this variant is classified as Likely Pathogenic.
Fundacion Hipercolesterolemia Familiar RCV000237585 SCV000607640 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Iberoamerican FH Network RCV000237585 SCV000748099 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000588105 SCV000697210 pathogenic Familial hypercholesterolemias 2016-06-15 criteria provided, single submitter clinical testing Variant summary: The LDLR c.1783C>T (p.Arg595Trp) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/121410 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). This variant has been reported in numerous FH patients from multiple ethnic populations. In addition, p.R595Q and p.R595L have been shown to associate with FH, suggesting Arg595 is a mutation hot spot. Taken together, this variant is classified as pathogenic.
Invitae RCV000588105 SCV000752411 pathogenic Familial hypercholesterolemias 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 595 of the LDLR protein (p.Arg595Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs373371572, ExAC 0.001%). This variant has been observed in several individuals affected with familial hypercholesterolaemia (PMID: 11737238, 25461735, 27784735, 16250003, 20538126). ClinVar contains an entry for this variant (Variation ID: 161290). This variant disrupts the p.Arg595 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 15359125, 15256764, 16250003, 18718593, 25437892, 25487149, 27497240, 28502510), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
LDLR-LOVD, British Heart Foundation RCV000237585 SCV000295653 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237585 SCV000606512 pathogenic Familial hypercholesterolemia no assertion criteria provided research
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000237585 SCV000588606 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237585 SCV000494601 pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing

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