ClinVar Miner

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

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182342 SCV000234652 pathogenic not provided 2018-12-11 criteria provided, single submitter clinical testing The H583Y c.1747CAC>TAC mutation in the LDLR gene has been published previously as a disease-causing mutation using alternate nomenclature (reported as H562Y) (Sun et al., 1994; Van Hoof et al., 2005). Based on the ACMG recommendations, H583Y is interpreted as a known pathogenic sequence change. The variant is found in ,LDLR panel(s).
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 2019-12-27 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 2019-10-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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 2019-03-26 criteria provided, single submitter clinical testing The p.His583Tyr variant in LDLR (also reported as p.His562Tyr in the literature) has been reported in at least 18 individuals with familial hypercholesterolemia (FH): 15 in the heterozygous state and 3 in the compound heterozygous state. It segregated with disease in 9 affected relatives from 3 families (Sun 1994, Punzalan 2005, Chiou 2012, Yao 2012, Ma 2017). Compound heterozygotes were more severely affected than heterozygotes in the same families. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 200921) and has been identified in 0.13% (24/18868) of East Asian chromosomes by gnomAD ( This frequency in low enough to be consistent with the frequency of FH in the general population. In vitro functional studies provide some evidence that the p.His583Tyr variant may impact protein processing (Sun 1994). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon occurrences in multiple affected individuals, segregation studies and functional evidence. The ACMG/AMP Criteria applied: PS4; PP1_Strong; PS3_Supporting.
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

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