VCV000200921.45 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(25)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 200921 Accession: VCV000200921.45

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.2 19: 11116900 (GRCh38) [ NCBI UCSC ] 19: 11227576 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 21, 2016	Aug 11, 2024	Jul 18, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000527.5:c.1747C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000518.1:p.His583Tyr	missense
NM_001195798.2:c.1747C>T	NP_001182727.1:p.His583Tyr	missense
NM_001195799.2:c.1624C>T	NP_001182728.1:p.His542Tyr	missense
NM_001195800.2:c.1243C>T	NP_001182729.1:p.His415Tyr	missense
NM_001195803.2:c.1366C>T	NP_001182732.1:p.His456Tyr	missense
NC_000019.10:g.11116900C>T
NC_000019.9:g.11227576C>T
NG_009060.1:g.32520C>T
LRG_274:g.32520C>T
LRG_274t1:c.1747C>T	LRG_274p1:p.His583Tyr

... more HGVS ... less HGVS

Protein change

H583Y, H456Y, H542Y, H415Y

Other names

p.H583Y:CAC>TAC
NP_000518.1:p.H583Y

Canonical SPDI

NC_000019.10:11116899:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD) 0.00003

Links

ClinGen: CA023567 LDLR-LOVD, British Heart Foundation: LDLR_000234 dbSNP: rs730882109 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
LDLR		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	4085	4361

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	May 1, 2023	RCV000182342.11
Hypercholesterolemia, familial, 1	Pathogenic/Likely pathogenic (12)	criteria provided, multiple submitters, no conflicts	Jan 4, 2024	RCV000211604.22
Familial hypercholesterolemia	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Jul 18, 2024	RCV000771547.21
Homozygous familial hypercholesterolemia	Pathogenic (1)	criteria provided, single submitter	Dec 16, 2020	RCV000825621.6
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Apr 30, 2024	RCV002399654.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Mar 25, 2016)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: literature only	Familial hypercholesterolemia (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	LDLR-LOVD, British Heart Foundation Accession: SCV000295633.2 First in ClinVar: Jul 29, 2016 Last updated: Sep 30, 2017	Publications: PubMed (3) PubMed: 16205024‚ 20538126‚ 7903864 Observation 1: Number of individuals with the variant: 1 Observation 2: Number of individuals with the variant: 1 Observation 3: Number of individuals with the variant: 1
Likely pathogenic (-)	criteria provided, single submitter (Wang et al. (Arterioscler Thromb Vasc Biol. 2016)) Method: clinical testing	Hypercholesterolemia, familial, 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Robarts Research Institute, Western University Accession: SCV000484707.1 First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016	Number of individuals with the variant: 2
Pathogenic (Mar 30, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial Hypercholesterolemia Affected status: yes Allele origin: germline	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille Accession: SCV000583880.1 First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016 Comment: ACMG Guidelines: Pathogenic (ii)	Number of individuals with the variant: 2 Clinical Features: Hyperbetalipoproteinemia (present) , Hypercholesterolemia (present) Indication for testing: Familial Hypercholesterolemia Sex: mixed Geographic origin: France Comment on evidence: Dutch Lipid Clinic Scoring : Definite FH Secondary finding: no
Pathogenic (Mar 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation, literature only	Familial hypercholesterolemia (Autosomal dominant inheritance) Affected status: unknown, not applicable Allele origin: germline, not applicable	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge Accession: SCV000599392.1 First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017	Publications: PubMed (2) PubMed: 21511053‚ 7903864 Observation 1: Comment on evidence: %MAF(ExAC):0.009061 Observation 2: Comment on evidence: Assay Description:Retrovirus transfected LDLR-/- fibroblasts, FACS and 125I-LDL assays / Heterologous cells (COS), immunoblot Result: ~50% cell surface LDLR, 50-60% LDL-LDLR uptake, normal LDL-LDLR binding / ~50% mature protein, binds LDL
Pathogenic (Dec 13, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000234652.14 First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Likely pathogenic (Jan 23, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hypercholesterolemia, familial, 1 Affected status: yes, unknown Allele origin: unknown	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: AGHI-GT-HudsonAlpha Accession: SCV000778597.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017	Observation 1: Number of individuals with the variant: 1 Observation 2: Number of individuals with the variant: 1
Likely pathogenic (Jun 05, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hypercholesterolemia, familial, 1 Affected status: yes Allele origin: germline	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia Accession: SCV001432592.1 First in ClinVar: Sep 19, 2020 Last updated: Sep 19, 2020	Number of individuals with the variant: 1 Clinical Features: Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
Pathogenic (Dec 16, 2020)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Homozygous familial hypercholesterolemia (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000966973.3 First in ClinVar: Aug 26, 2019 Last updated: May 29, 2021	Publications: PubMed (9) PubMed: 7903864‚ 16205024‚ 22353362‚ 23155708‚ 29233637‚ 30526649‚ 30586733‚ 30592178‚ 31491741 Comment: proposed classification - variant undergoing re-assessment, contact laboratory Number of individuals with the variant: 1
Pathogenic (Jun 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002503309.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (13) PubMed: 7903864‚ 30526649‚ 30592178‚ 32041611‚ 32719484‚ 31491741‚ 30586733‚ 29233637‚ 32800790‚ 32331935‚ 23155708‚ 21511053‚ 31447099 Number of individuals with the variant: 1 Secondary finding: no
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002516655.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Pathogenic (Jun 16, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000917579.2 First in ClinVar: Jun 02, 2019 Last updated: Aug 03, 2022	Publications: PubMed (4) PubMed: 7903864‚ 21511053‚ 22353362‚ 29233637 Comment: 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 … (more) 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. (less)
Pathogenic (May 01, 2023)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV001470531.2 First in ClinVar: Jan 26, 2021 Last updated: Jan 06, 2024	Publications: PubMed (20) PubMed: 32041611‚ 32719484‚ 32154576‚ 32331935‚ 32800790‚ 32759540‚ 34037665‚ 33569482‚ 33994402‚ 35741760‚ 29233637‚ 23155708‚ 30592178‚ 30586733‚ 30526649‚ 22353362‚ 27206935‚ 29353225‚ 15741231‚ 7903864 Comment: 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 … (more) 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. (less)
Pathogenic (Dec 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002017115.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Oct 12, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000904108.5 First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024	Publications: PubMed (15) PubMed: 7903864‚ 15494314‚ 15741231‚ 16205024‚ 20538126‚ 22353362‚ 23155708‚ 29233637‚ 30949068‚ 32695144‚ 32759540‚ 33418990‚ 33746137‚ 36011335‚ 36172582 Comment: 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. … (more) 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. (less)
Pathogenic (Jan 20, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000752419.7 First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024	Publications: PubMed (11) PubMed: 7903864‚ 16205024‚ 21376320‚ 22353362‚ 23155708‚ 27206935‚ 28028493‚ 21511053‚ 19318025‚ 22698793‚ 23375686 Comment: 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). … (more) 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. (less)
Pathogenic (Feb 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypercholesterolemia (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Molecular Genetics, Royal Melbourne Hospital Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004812534.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Publications: PubMed (10) PubMed: 7903864‚ 21511053‚ 22353362‚ 23155708‚ 26608663‚ 29233637‚ 32695144‚ 33569482‚ 33746137‚ 33994402 Comment: 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 … (more) 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. (less)
Pathogenic (Jan 04, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 1 (Semidominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004822494.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (15) PubMed: 7903864‚ 15494314‚ 15741231‚ 16205024‚ 20538126‚ 22353362‚ 23155708‚ 29233637‚ 30949068‚ 32695144‚ 32759540‚ 33418990‚ 33746137‚ 36011335‚ 36172582 Comment: 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. … (more) 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. (less) Number of individuals with the variant: 3
Likely pathogenic (Jul 18, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial hypercholesterolemia (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine Accession: SCV001482454.2 First in ClinVar: Mar 07, 2021 Last updated: Aug 04, 2024	Publications: PubMed (10) PubMed: 25741868‚ 32015373‚ 32695144‚ 7903864‚ 34456200‚ 33533259‚ 33994402‚ 33418990‚ 21520341‚ 33261662 DOI: 10.1016/j.gim.2021.09.012 DOI: 10.1016/j.gim.2021.09.012 DOI: 10.18699/VJGB-22-38 DOI: 10.18699/VJGB-22-38 DOI: 10.3389/fcvm.2022.994662 DOI: 10.3389/fcvm.2022.994662 DOI: 10.4068/cmj.2018.54.1.31 DOI: 10.4068/cmj.2018.54.1.31 DOI: 10.1186/s12872-024-03759-5 DOI: 10.1186/s12872-024-03759-5 Comment: 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 … (more) 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) (less) Age: 40-49 years Sex: female
Pathogenic (Apr 30, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002711608.3 First in ClinVar: Nov 29, 2022 Last updated: Aug 11, 2024	Publications: PubMed (19) PubMed: 7903864‚ 19318025‚ 20538126‚ 21376320‚ 22353362‚ 22698793‚ 22883975‚ 23155708‚ 23375686‚ 25846081‚ 27206935‚ 28028493‚ 28475941‚ 29233637‚ 29399563‚ 32331935‚ 32800790‚ 36011335‚ 37805670 Comment: 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 … (more) 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. (less)
Pathogenic (Oct 19, 2010)	no assertion criteria provided Method: clinical testing	Familial hypercholesterolemia Affected status: yes Allele origin: germline	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital Accession: SCV000268636.1 First in ClinVar: May 21, 2016 Last updated: May 21, 2016	Number of individuals with the variant: 3
Pathogenic (-)	no assertion criteria provided Method: research	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum Accession: SCV000606503.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001461316.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001924783.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001971024.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Likely benign (Dec 16, 2016)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: clinical testing Reason: Older and outlier claim with insufficient supporting evidence Source: ClinGen	Hypercholesterolemia, familial, 1 Affected status: yes Allele origin: germline	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix Accession: SCV000503407.1 First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016	Comment: subject mutated among 2600 FH index cases screened = 1 /previously described in association with FH /Software predictions: Conflicting Number of individuals with the variant: 1
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Comment:

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)

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Rare and common coding variants in lipid metabolism-related genes and their association with coronary artery disease.	Li W	BMC cardiovascular disorders	2024	DOI: 10.1186/s12872-024-03759-5
Prevalence and prognosis of genetically proven familial hypercholesterolemia in subjects with coronary artery disease and reduced ejection fraction.	Lee WJ	Scientific reports	2023	PMID: 37805670
Prevalence of genetically defined familial hypercholesterolemia and the impact on acute myocardial infarction in Taiwanese population: A hospital-based study.	Chen YJ	Frontiers in cardiovascular medicine	2022	DOI: 10.3389/fcvm.2022.994662
Prevalence of genetically defined familial hypercholesterolemia and the impact on acute myocardial infarction in Taiwanese population: A hospital-based study.	Chen YJ	Frontiers in cardiovascular medicine	2022	PMID: 36172582
Identification of New Copy Number Variation and the Evaluation of a CNV Detection Tool for NGS Panel Data in Polish Familial Hypercholesterolemia Patients.	Rutkowska L	Genes	2022	PMID: 36011335
Analysis of the low density lipoprotein receptor gene (LDLR) mutation spectrum in Russian familial hypercholesterolemia.	Vasilyev VB	Vavilovskii zhurnal genetiki i selektsii	2022	DOI: 10.18699/VJGB-22-38
Identification of New Genetic Determinants in Pediatric Patients with Familial Hypercholesterolemia Using a Custom NGS Panel.	Rutkowska L	Genes	2022	PMID: 35741760
Phenotypic and Genetic Analyses of Korean Patients with Familial Hypercholesterolemia: Results from the KFH Registry 2020.	Kim H	Journal of atherosclerosis and thrombosis	2022	PMID: 34456200
Genetic Analysis in a Taiwanese Cohort of 750 Index Patients with Clinically Diagnosed Familial Hypercholesterolemia.	Huang CC	Journal of atherosclerosis and thrombosis	2022	PMID: 33994402
Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis.	Sturm AC	JAMA cardiology	2021	PMID: 34037665
Familial Hypercholesterolemia in Asia Pacific: A Review of Epidemiology, Diagnosis, and Management in the Region.	Kalra S	Journal of atherosclerosis and thrombosis	2021	PMID: 33746137
Identifying familial hypercholesterolemia in an early onset ischemic cerebrovascular disease patient and the cascade screening in the pedigree: a case report.	Yuan Y	Annals of translational medicine	2021	PMID: 33569482
Patients With LDLR and PCSK9 Gene Variants Experienced Higher Incidence of Cardiovascular Outcomes in Heterozygous Familial Hypercholesterolemia.	Doi T	Journal of the American Heart Association	2021	PMID: 33533259
The LDLR, APOB, and PCSK9 Variants of Index Patients with Familial Hypercholesterolemia in Russia.	Meshkov A	Genes	2021	PMID: 33418990
dbNSFP v4: a comprehensive database of transcript-specific functional predictions and annotations for human nonsynonymous and splice-site SNVs.	Liu X	Genome medicine	2020	PMID: 33261662
Successful pharmacological management of a child with compound heterozygous familial hypercholesterolemia and review of the recent literature.	Sreedharan AV	Journal of clinical lipidology	2020	PMID: 32800790
Targeted Genetic Analysis in a Chinese Cohort of 208 Patients Related to Familial Hypercholesterolemia.	Wang H	Journal of atherosclerosis and thrombosis	2020	PMID: 32759540
Population genetic screening efficiently identifies carriers of autosomal dominant diseases.	Grzymski JJ	Nature medicine	2020	PMID: 32719484
Low Density Lipoprotein Receptor Variants in the Beta-Propeller Subdomain and Their Functional Impact.	Dušková L	Frontiers in genetics	2020	PMID: 32695144
A catalog of the pathogenic mutations of LDL receptor gene in Japanese familial hypercholesterolemia.	Tada H	Journal of clinical lipidology	2020	PMID: 32331935
Exploring the genetic pathogenicity of aortic dissection from 72 Han Chinese individuals using next-generation sequencing.	Pan M	Clinical genetics	2020	PMID: 32154576
Six years' experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias.	Dron JS	BMC medical genomics	2020	PMID: 32041611
Mutation type classification and pathogenicity assignment of sixteen missense variants located in the EGF-precursor homology domain of the LDLR.	Galicia-Garcia U	Scientific reports	2020	PMID: 32015373
Impact of LDLR and PCSK9 pathogenic variants in Japanese heterozygous familial hypercholesterolemia patients.	Hori M	Atherosclerosis	2019	PMID: 31491741
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network.	eMERGE Consortium. Electronic address: [email protected]	American journal of human genetics	2019	PMID: 31447099
Current Status of Familial Hypercholesterolemia in China: A Need for Patient FH Registry Systems.	Chen P	Frontiers in physiology	2019	PMID: 30949068
Genetic variations in familial hypercholesterolemia and cascade screening in East Asians.	Chan ML	Molecular genetics & genomic medicine	2019	PMID: 30592178
Whole-Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized With Early-Onset Myocardial Infarction.	Khera AV	Circulation	2019	PMID: 30586733
Application of expanded genetic analysis in the diagnosis of familial hypercholesterolemia in patients with very early-onset coronary artery disease.	Cao YX	Journal of translational medicine	2018	PMID: 30526649
Detection of Familial Hypercholesterolemia Using Next Generation Sequencing in Two Population-Based Cohorts.	Kim HN	Chonnam medical journal	2018	DOI: 10.4068/cmj.2018.54.1.31
Detection of Familial Hypercholesterolemia Using Next Generation Sequencing in Two Population-Based Cohorts.	Kim HN	Chonnam medical journal	2018	PMID: 29399563
Spectrum of mutations in index patients with familial hypercholesterolemia in Singapore: Single center study.	Pek SLT	Atherosclerosis	2018	PMID: 29353225
Compound heterozygous familial hypercholesterolemia in a Chinese boy with a de novo and transmitted low-density lipoprotein receptor mutation.	Ma Y	Journal of clinical lipidology	2018	PMID: 29233637
Mutational analysis and genotype-phenotype relation in familial hypercholesterolemia: The SAFEHEART registry.	Bourbon M	Atherosclerosis	2017	PMID: 28475941
Mutation detection in Chinese patients with familial hypercholesterolemia.	Du R	SpringerPlus	2016	PMID: 28028493
Genetic diagnosis of familial hypercholesterolemia in Han Chinese.	Chiou KR	Journal of clinical lipidology	2016	PMID: 27206935
The distribution and characteristics of LDL receptor mutations in China: A systematic review.	Jiang L	Scientific reports	2015	PMID: 26608663
Novel mutations of low-density lipoprotein receptor gene in China patients with familial hypercholesterolemia.	Fan LL	Applied biochemistry and biotechnology	2015	PMID: 25846081
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy.	Bertolini S	Atherosclerosis	2013	PMID: 23375686
Identification of LDLR mutations in two Chinese pedigrees with familial hypercholesterolemia.	Yao RE	Journal of pediatric endocrinology & metabolism : JPEM	2012	PMID: 23155708
Genetic analysis of familial hypercholesterolaemia in Western Australia.	Hooper AJ	Atherosclerosis	2012	PMID: 22883975
The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations.	Tichý L	Atherosclerosis	2012	PMID: 22698793
Common mutations of familial hypercholesterolemia patients in Taiwan: characteristics and implications of migrations from southeast China.	Chiou KR	Gene	2012	PMID: 22353362
dbNSFP: a lightweight database of human nonsynonymous SNPs and their functional predictions.	Liu X	Human mutation	2011	PMID: 21520341
Role of an intramolecular contact on lipoprotein uptake by the LDL receptor.	Zhao Z	Biochimica et biophysica acta	2011	PMID: 21511053
Array-based resequencing for mutations causing familial hypercholesterolemia.	Chiou KR	Atherosclerosis	2011	PMID: 21376320
Detection of mutations and large rearrangements of the low-density lipoprotein receptor gene in Taiwanese patients with familial hypercholesterolemia.	Chiou KR	The American journal of cardiology	2010	PMID: 20538126
Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform.	Alonso R	Clinical biochemistry	2009	PMID: 19318025
Low density lipoprotein--receptor (LDL-R) gene mutations among Filipinos with familial hypercholesterolemia.	Punzalan FE	Journal of atherosclerosis and thrombosis	2005	PMID: 16205024
Intracellular fate of LDL receptor family members depends on the cooperation between their ligand-binding and EGF domains.	Van Hoof D	Journal of cell science	2005	PMID: 15741231
Cooperation between fixed and low pH-inducible interfaces controls lipoprotein release by the LDL receptor.	Beglova N	Molecular cell	2004	PMID: 15494314
Familial hypercholesterolemia in China. Identification of mutations in the LDL-receptor gene that result in a receptor-negative phenotype.	Sun XM	Arteriosclerosis and thrombosis : a journal of vascular biology	1994	PMID: 7903864
-	-	-	-	DOI: 10.1016/j.gim.2021.09.012
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Text-mined citations for rs730882109 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs730882109 ...