ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1747C>T (p.His583Tyr) (rs730882109)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182342 SCV000234652 pathogenic not provided 2021-03-25 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate that this variant causes receptor-ligand complex degradation, with cells expressing this variant producing only about 50% mature protein and showing reduced surface expression of receptors (Sun et al., 1994; Van Hoof et al., 2005; Zhao et al., 2011); Also denoted as H562Y due to the use of alternate nomenclature; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#200921; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 23155708, 33569482, 33418990, 32759540, 33223521, 32695144, 32800790, 31447099, 29233637, 28235710, 25846081, 31491741, 15494314, 30586733, 30592178, 30526649, 27206935, 28028493, 30270083, 21511053, 22353362, 15741231, 20538126, 7903864, 16205024, 21376320)
LDLR-LOVD, British Heart Foundation RCV000211604 SCV000295633 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000211604 SCV000484707 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000211604 SCV000503407 likely benign Familial hypercholesterolemia 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 /Software predictions: Conflicting
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000211604 SCV000583880 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000211604 SCV000599392 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter curation
Invitae RCV000771547 SCV000752419 pathogenic Familial hypercholesterolemia 2020-09-22 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 583 of the LDLR protein (p.His583Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs730882109, ExAC 0.09%). This variant is a known familial hypercholesterolemia founder variant in China and it has been reported in multiple unrelated affected individuals and segregating with disease in a family in China and Southeast Asia (PMID: 7903864, 23155708, 27206935, 21376320, 22353362, 28028493, 16205024). This variant is also known as p.His562Tyr in the literature. ClinVar contains an entry for this variant (Variation ID: 200921). Experimental studies have shown that this missense change impairs lipoprotein uptake by reducing the number of surface receptors (PMID: 7903864, 21511053). Different missense substitution at this codon (p.His583Gln, p.His583Asp, His583Arg) have been reported in several individuals affected with hypercholesterolemia (PMID: 23375686, 19318025, 22698793). This suggests that the histidine residue is critical for LDLR protein function and that other missense substitutions at this position may be deleterious. For these reasons, this variant has been classified as Pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000211604 SCV000778597 likely pathogenic Familial hypercholesterolemia 1 2018-01-23 criteria provided, single submitter research
Color Health, Inc RCV000771547 SCV000904108 likely pathogenic Familial hypercholesterolemia 2020-12-21 criteria provided, single submitter clinical testing This missense variant (also known as His562Tyr in the mature protein) His583Tyr replaces histidine with tyrosine at codon 583 of the fifth LDLR type B repeat of the EGF precursor homology domain of the LDLR protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold ‚â•0.7, PMID: 27666373). A functional study has shown that the mutant LDLR retains the ability to bind LDL at neutral pH on the cell surface and releases bound LDL in response to low pH, but at a lower rate (PMID: 15494314). Another functional study has shown that the variant does not affect constitutive LDLR recycling in the absence of LDL but causes 50% reduction in recycling of LDLR when bound to LDL (PMID: 15741231). A third study indicated that the variant may impact protein processing (PMID: 7903864). This variant has been reported in multiple Asian individuals affected with familial hypercholesterolemia (PMID: 32759540, 29233637, 23155708, 22353362, 20538126, 16205024, 7903864) and segregated with disease in multiple families (PMID: 29233637, 23155708, 22353362). Additionally, compound heterozygote individuals demonstrated a more severe phenotype than heterozygotes with this variant. In China, this variant is one of the three LDLR mutations that are present in 23% of probands affected with familial hypercholesterolemia (PMID: 30949068). The variant has been identified in 29/282882 chromosomes (24/19952 East Asian chromosomes) by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000771547 SCV000917579 pathogenic Familial hypercholesterolemia 2018-04-30 criteria provided, single submitter clinical testing Variant summary: LDLR c.1747C>T (p.His583Tyr) results in a conservative amino acid change located in the LDLR class B repeat of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 277230 control chromosomes. This frequency is not higher than expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (0.0001 vs 0.0013), allowing no conclusion about variant significance. c.1747C>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia and is reported as a common mutation in Chinese/East Asian populations. These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating LDLR expression, cell surface localization, and LDL uptake, and all results suggest a partial deficiency of ~50% of normal activity. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825621 SCV000966973 pathogenic Homozygous familial hypercholesterolemia 2020-12-16 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000211604 SCV001432592 likely pathogenic Familial hypercholesterolemia 1 2019-06-05 criteria provided, single submitter research
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000182342 SCV001470531 pathogenic not provided 2019-10-31 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. Statistically associated with disease in a single family.
Laboratory of Molecular Genetics,National Medical Research Center for Therapy and Preventive Medicine RCV000771547 SCV001482454 uncertain significance Familial hypercholesterolemia criteria provided, single submitter research
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211604 SCV000268636 pathogenic Familial hypercholesterolemia 1 2010-10-19 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211604 SCV000606503 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Natera, Inc. RCV000771547 SCV001461316 pathogenic Familial hypercholesterolemia 2020-09-16 no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000182342 SCV001924783 pathogenic not provided no assertion criteria provided clinical testing

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