ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1747C>T (p.His583Tyr) (rs730882109)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 13
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211604 SCV000268636 pathogenic Familial hypercholesterolemia 2010-10-19 no assertion criteria provided clinical testing
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000211604 SCV000599392 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter curation
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 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
Color RCV000771547 SCV000904108 likely pathogenic Familial hypercholesterolemias 2018-07-22 criteria provided, single submitter clinical testing Likely Pathogenic variant based on current evidence: This missense variant (also known as His562Tyr 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 are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. An experimental 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 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). These studies suggest possible deleterious impact of the variant on LDLR function. This variant has also been reported in multiple Asian individuals affected with familial hypercholesterolemia (PMID: 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. The variant appears to be a recurrent allele in Asian populations having been identified in 29/18868 Asian chromosomes by the Genome Aggregation Database (gnomAD). Based on available evidence and the observed frequency of this variant in the general population, this variant is classified as Likely Pathogenic with possible low penetrance.
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).
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000211604 SCV000778597 likely pathogenic Familial hypercholesterolemia 2018-01-23 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000771547 SCV000917579 pathogenic Familial hypercholesterolemias 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.
Invitae RCV000771547 SCV000752419 pathogenic Familial hypercholesterolemias 2018-10-15 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.
LDLR-LOVD, British Heart Foundation RCV000211604 SCV000295633 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211604 SCV000606503 pathogenic Familial hypercholesterolemia no assertion criteria provided research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000825621 SCV000966973 pathogenic Familial hypercholesterolemia - homozygous 2018-01-08 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, Punz alan 2005, Chiou 2012, Yao 2012, Ma 2017). Compound heterozygotes were more seve rely affected than heterozygotes in the same families. This variant has also bee n 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 (htt p://gnomad.broadinstitute.org). This frequency in low enough to be consistent wi th the frequency of FH in the general population. In vitro functional studies pr ovide some evidence that the p.His583Tyr variant may impact protein processing ( Sun 1994). Computational prediction tools and conservation analysis do not provi de strong support for or against an impact to the protein. In summary, this vari ant meets criteria to be classified as pathogenic for FH in an autosomal dominan t manner based upon occurrences in multiple affected individuals, segregation st udies and functional evidence. ACMG/AMP Criteria applied: PS4; PP1_Strong; PS3_S upporting.
Robarts Research Institute,Western University RCV000211604 SCV000484707 likely pathogenic Familial hypercholesterolemia criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000211604 SCV000583880 pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.