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

gnomAD frequency: 0.00003  dbSNP: rs730882109

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182342	SCV000234652	pathogenic	not provided	2021-12-13	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 known as H562Y; This variant is associated with the following publications: (PMID: 16205024, 30270083, 21376320, 31491741, 7903864, 20538126, 15741231, 22353362, 21511053, 28028493, 27206935, 23155708, 30526649, 30592178, 30586733, 15494314, 29233637, 25846081, 28235710, 31447099, 32800790, 33223521, 32759540, 32695144, 33418990, 33569482, 32041611, 32719484, 32154576, 32331935, 34037665, 33994402, 34526433, 34573395, 34176852)
LDLR-LOVD, British Heart Foundation	RCV000211604	SCV000295633	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000211604	SCV000484707	likely pathogenic	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000211604	SCV000599392	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	curation
Invitae	RCV000771547	SCV000752419	pathogenic	Familial hypercholesterolemia	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 583 of the LDLR protein (p.His583Tyr). This variant is present in population databases (rs730882109, gnomAD 0.1%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 7903864, 16205024, 21376320, 22353362, 23155708, 27206935, 28028493). It is commonly reported in individuals of Chinese and Southeast Asian ancestry (PMID: 7903864, 16205024, 21376320, 22353362, 23155708, 27206935, 28028493). This variant is also known as p.His562Tyr. ClinVar contains an entry for this variant (Variation ID: 200921). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LDLR function (PMID: 7903864, 21511053). This variant disrupts the p.His583 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19318025, 22698793, 23375686). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000211604	SCV000778597	likely pathogenic	Hypercholesterolemia, familial, 1	2018-01-23	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000771547	SCV000904108	pathogenic	Familial hypercholesterolemia	2023-10-12	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 583 of the LDLR protein. This variant is also known as p.His562Tyr in the mature protein. This variant alters a conserved histidine residue in the fifth LDLR type B repeat of the EGF precursor homology domain of the LDLR protein (a.a. 572-615), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tool suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes partially defective protein processing and trafficking to the plasma membrane (PMID: 7903864, 32695144), decrease in LDL internalization (PMID: 32695144), and reduction in recycling of LDLR when bound to LDL (PMID: 15494314, 15741231). This variant has been observed in over fifty individuals affected with familial hypercholesterolemia, mostly of East Asian ancestry (PMID: 7903864, 16205024, 20538126, 22353362, 23155708, 29233637, 30949068, 32759540, 33418990, 33746137, 36011335, 36172582; Color internal data). This variant has been reported to segregate with disease in two families (PMID: 22353362, 23155708). Individuals who were compound heterozygous for this variant and other pathogenic variant in the same gene have shown a more severe phenotype than heterozygous carriers of this variant (PMID: 7903864, 20538126, 23155708, 29233637, 36011335). This 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 Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000771547	SCV000917579	pathogenic	Familial hypercholesterolemia	2022-06-16	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 0.00011 in 251488 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (0.00011 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. Fourteen ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and one ClinVar submitter (evaluation after 2014) cites it as likely benign. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham 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	Hypercholesterolemia, familial, 1	2019-06-05	criteria provided, single submitter	research
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000182342	SCV001470531	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0012 (24/19952 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported as a common familial hypercholesterolemia (FH) variant within the Chinese and East Asian populations (PMIDs: 33994402 (2021), 32759540 (2020), 32331935 (2020), 32800790 (2020), 30592178 (2019), 27206935 (2016), 23155708 (2012), 22353362 (2012), 7903864 (1994)). Additionally, the variant has been reported in individuals with FH across multiple ethnicities (PMIDs: 35741760 (2022), 33569482 (2021), 34037665 (2021), 32041611 (2020), 30526649 (2018), 29233637 (2018)). A functional study found that the presence of this variant is damaging to proper LDLR function (PMID: 15741231 (2005)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine	RCV000771547	SCV001482454	likely pathogenic	Familial hypercholesterolemia	2024-07-18	criteria provided, single submitter	research	Based on the ACMG/AMP 2015 guidelines (Richards 2015), the His583Tyr variant has the following pathogenicity criteria: PM1- is located in the EGF-precursor homology domain: YWTD repeat (Galicia-Garcia 2020). Has a deleterious effect on protein localization and function (Dušková 2020, Sun 1994). His583 is localised on the interface between the beta-propeller and the ligand-binding repeat R5. Most probably, the variant p.His583Tyr, resulting in loss of charge, will have a more severe effect on the protein structure than p.His583Arg (Dušková 2020); PM2 - detected in control samples of gnomAD v4.1.0 with a frequency of 0.002788%; PP3; PP4-registered in patients with FH. According to the ClinGen guidelines for LDLR variant classification (Chora 2022), PS4 - variant is found in ≥10 unrelated FH cases, including 2 FH cases in Russia (Kim 2022 (n = 1), Doi 2021 (n=1), Huang 2022 (n=1), Chiou 2010 (n=6), Meshkov 2021 and Vasilyev 2022 (n = 2)); PM2 - has a PopMax MAF ≤ 0.0002 (0.02%) in gnomAD (0.002788% v4.1.0 gnomAD); PP3 - REVEL score 0.884 (Liu 2011, Liu 2020); PP4 - identified in 6 probands with FH based on Simon Broome criteria (Chiou 2010), and in 1 proband with FH based on DLCN-criteria (data from the Laboratory of Molecular Genetics, Moscow, Russia (Meshkov 2021)). Based on a combination of criteria, this variant is likely pathogenic. p.His583Tyr has been verified in cohorts with coronary heart disease (Chen 2022, Kim 2018, Li 2024) including in 230 subjects from the Chen 2022 study. p.His583Tyr associated with an approximately 4-fold increased risk of acute myocardial infarction compared with individuals without this variant (p<0 .0001) (Chen 2022)
Revvity Omics, Revvity	RCV000211604	SCV002017115	pathogenic	Hypercholesterolemia, familial, 1	2022-12-05	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000182342	SCV002503309	pathogenic	not provided	2021-06-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000211604	SCV002516655	pathogenic	Hypercholesterolemia, familial, 1	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399654	SCV002711608	pathogenic	Cardiovascular phenotype	2024-04-30	criteria provided, single submitter	clinical testing	The c.1747C>T (p.H583Y) alteration is located in exon 12 (coding exon 12) of the LDLR gene. This alteration results from a C to T substitution at nucleotide position 1747, causing the histidine (H) at amino acid position 583 to be replaced by a tyrosine (Y). Based on data from gnomAD, the T allele has an overall frequency of 0.01% (29/282882) total alleles studied. The highest observed frequency was 0.12% (24/19952) of East Asian alleles. This alteration (also described as legacy p.H562Y) has been described as a Taiwanese and Chinese founder mutation and has been reported in the heterozygous state, and in conjunction with another alteration in LDLR, in multiple individuals with familial hypercholesterolemia (FH) and has been reported to segregate with disease in several families (Lee, 2023; Tada, 2020; Kim, 2018; Du, 2016; Fan, 2015; Chiou, 2011; Chiou, 2010; Rutkowska, 2022; Sreedharan, 2020; Ma, 2018; Yao, 2012; Sun, 1994; Chiou, 2012). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Molecular Genetics, Royal Melbourne Hospital	RCV000771547	SCV004812534	pathogenic	Familial hypercholesterolemia	2024-02-05	criteria provided, single submitter	clinical testing	This sequence change in LDLR is predicted to replace histidine with tyrosine at codon 583, p.(His583Tyr). The histidine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in LDL-receptor class B repeat 5. There is a moderate physicochemical difference between histidine and tyrosine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.05% (22/44,896 alleles) in the East Asian population and is a known Chinese/East Asian founder variant for familial hypercholesterolaemia (FH, PMID: 26608663, 33746137). The variant has been reported to segregate with FH in multiple families (PMID: 22353362, 23155708, 29233637, 33569482, 33994402). The variant has been detected in the homozygous and compound heterozygous state in multiple individuals with a phenotype consistent with biallelic FH (PMID: 7903864, 23155708, 29233637, 33569482, 33994402). Functional studies demonstrate a damaging effect with defective protein processing and trafficking to the plasma membrane and decreased LDL internalisation (PMID: 21511053, 32695144). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.884). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PS3, PP1_Strong, PM3, PP3.
All of Us Research Program, National Institutes of Health	RCV000211604	SCV004822494	pathogenic	Hypercholesterolemia, familial, 1	2024-01-04	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 583 of the LDLR protein. This variant is also known as p.His562Tyr in the mature protein. This variant alters a conserved histidine residue in the fifth LDLR type B repeat of the EGF precursor homology domain of the LDLR protein (a.a. 572-615), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tool suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Functional studies have shown that this variant causes partially defective protein processing and trafficking to the plasma membrane (PMID: 7903864, 32695144), decrease in LDL internalization (PMID: 32695144), and reduction in recycling of LDLR when bound to LDL (PMID: 15494314, 15741231). This variant has been observed in over fifty individuals affected with familial hypercholesterolemia, mostly of East Asian ancestry (PMID: 7903864, 16205024, 20538126, 22353362, 23155708, 29233637, 30949068, 32759540, 33418990, 33746137, 36011335, 36172582; Color internal data). This variant has been reported to segregate with disease in two families (PMID: 22353362, 23155708). Individuals who were compound heterozygous for this variant and other pathogenic variant in the same gene have shown a more severe phenotype than heterozygous carriers of this variant (PMID: 7903864, 20538126, 23155708, 29233637, 36011335). This 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 Pathogenic.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211604	SCV000268636	pathogenic	Hypercholesterolemia, familial, 1	2010-10-19	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211604	SCV000606503	pathogenic	Hypercholesterolemia, familial, 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
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000182342	SCV001971024	pathogenic	not provided		no assertion criteria provided	clinical testing