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

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Jul 18, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000771547.21

Allele description [Variation Report for NM_000527.5(LDLR):c.1747C>T (p.His583Tyr)]

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

Gene:

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

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

Other names:

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

HGVS:

NC_000019.10:g.11116900C>T
NG_009060.1:g.32520C>T
NM_000527.5:c.1747C>TMANE SELECT
NM_001195798.2:c.1747C>T
NM_001195799.2:c.1624C>T
NM_001195800.2:c.1243C>T
NM_001195803.2:c.1366C>T
NP_000518.1:p.His583Tyr
NP_000518.1:p.His583Tyr
NP_001182727.1:p.His583Tyr
NP_001182728.1:p.His542Tyr
NP_001182729.1:p.His415Tyr
NP_001182732.1:p.His456Tyr
LRG_274t1:c.1747C>T
LRG_274:g.32520C>T
LRG_274p1:p.His583Tyr
NC_000019.9:g.11227576C>T
NM_000527.4:c.1747C>T
c.1747C>T

Protein change:

H415Y

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000234; dbSNP: rs730882109

NCBI 1000 Genomes Browser:

rs730882109

Molecular consequence:

NM_000527.5:c.1747C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1747C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1624C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1243C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1366C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000752419	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 20, 2024)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 16205024, 21376320, 22353362, 23155708, 27206935, 28028493, 7903864, 21511053, 19318025, 22698793, 23375686, 28492532
SCV000904108	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 12, 2023)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 7903864, 15494314, 15741231, 16205024, 20538126, 22353362, 23155708, 29233637, 30949068, 32695144, 32759540, 33418990, 33746137, 36011335, 36172582, 25741868
SCV000917579	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 16, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 7903864, 21511053, 22353362, 29233637 Citation Link,
SCV001461316	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001482454	Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 18, 2024)	germline	research	PubMed (10) [See all records that cite these PMIDs] 32015373, 32695144, 7903864, 34456200, 33533259, 33994402, 33418990, 21520341, 33261662, 25741868
SCV004812534	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 5, 2024)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 7903864, 21511053, 22353362, 23155708, 26608663, 29233637, 32695144, 33569482, 33746137, 33994402, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Array-based resequencing for mutations causing familial hypercholesterolemia.

Chiou KR, Charng MJ, Chang HM.

Atherosclerosis. 2011 Jun;216(2):383-9. doi: 10.1016/j.atherosclerosis.2011.02.006. Epub 2011 Mar 3.

PubMed [citation]

PMID:: 21376320

Genetic diagnosis of familial hypercholesterolemia in Han Chinese.

Chiou KR, Charng MJ.

J Clin Lipidol. 2016 May-Jun;10(3):490-6. doi: 10.1016/j.jacl.2016.01.009. Epub 2016 Feb 19. Review.

PubMed [citation]

PMID:: 27206935

See all PubMed Citations (32)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000752419.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV000904108.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917579.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001461316.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine, SCV001482454.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (10)

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Molecular Genetics, Royal Melbourne Hospital, SCV004812534.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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