19-11116900-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3PS4PP1_StrongPM3PM2PP3PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1747C>T (p.His583Tyr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3, PS4, PP1_Strong, PM2, PM3, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.001203 (0.12%) in East Asian (gnomAD v2.1.1). PopMax MAF > 0.02% (PM2 is "not met"), however, after reviewing literature cases, a founder effect - mostly Asian ancestry - seems to be associated (PMID 27206935 - Chiou et al. 2016; several case reports used for PS4). This variant was also found in other populations: PopMax MAF = 0.016% in South Asian (gnomAD v2.1.1). PP3: REVEL = 0.884. PS3: Functional studies reported in PMID 32695144 (Dušková et al., 2020) performed using heterologous cells (CHO), WB and FACS - results - 52% expression and 44% internalization. The variant showed a deleterious effect on the protein localization and function, and was associated with the accumulation of the protein in the ER. Results are below 70%, so PS3 is met. // Functional studies reported in PMID 21511053 (Zhao et al., 2011) performed using retrovirus transfected LDLR-/- fibroblasts, FACS and 125I-LDL assays - results - approximately 50% cell surface LDLR, 50-60% LDL-LDLR uptake and normal LDL-LDLR binding. Results are below 70%, so PS3 is met. -------- Overall, both functional studies are consistent with damaging effect.PS4, PP4: Variant meets PM2 and is identified in at least 17 unrelated index cases fulfilling criteria for FH (2 index cases from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; at least 15 cases from PMID 20538126, 22353362, 21376320, 25846081, 19318025).PP1_Strong: Variant segregates with FH phenotype in at least 9 informative meioses (minimum 6) from 3 families from different PMIDs (23155708, 2923363, 22353362): 9 affected family members have the variant.PM3: Variant meets PM2 and is identified in 1 index case (PMID 7903864) with homozygous FH phenotype and a deletion of LDLR exons 4-11, confirmed in trans, classified as Pathogenic by these guidelines; 1 index case (PMID 23155708) with homozygous FH phenotype and the LDLR c.2054C>T, p.(Pro685Leu) variant, confirmed in trans, classified as Pathogenic by these guidelines; 1 index case (PMID 29233637) with homozygous FH phenotype and the LDLR c.724C>T, p.(Gln242*) variant, confirmed in trans, classified as Pathogenic by these guidelines. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023567/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 1 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:27B:1

Conservation

PhyloP100: 6.03

Publications

59 publications found

Variant links:

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

LDLR Gene-Disease associations (from GenCC):

hypercholesterolemia, familial, 1
Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
homozygous familial hypercholesterolemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LDLR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.1747C>T	p.His583Tyr	missense_variant	Exon 12 of 18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.1747C>T	p.His583Tyr	missense_variant	Exon 12 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000107

AC:

AN:

251488

AF XY:

0.000103

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00120

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1461782

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000453

AC:

AN:

39700

South Asian (SAS)

AF:

0.000174

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111940

Other (OTH)

AF:

0.000116

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000770

AC:

AN:

5196

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.555

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:27Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:13Benign:1

May 04, 2022

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1_Strong+PS4+PS3+PM5 -

Jun 05, 2019

Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Oct 19, 2010

Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Robarts Research Institute, Western University

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 07, 2023

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000527.5(LDLR):c.1747C>T (p.His583Tyr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3, PS4, PP1_Strong, PM2, PM3, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.001203 (0.12%) in East Asian (gnomAD v2.1.1). PopMax MAF > 0.02% (PM2 is "not met"), however, after reviewing literature cases, a founder effect - mostly Asian ancestry - seems to be associated (PMID 27206935 - Chiou et al. 2016; several case reports used for PS4). This variant was also found in other populations: PopMax MAF = 0.016% in South Asian (gnomAD v2.1.1). PP3: REVEL = 0.884. PS3: Functional studies reported in PMID 32695144 (Dušková et al., 2020) performed using heterologous cells (CHO), WB and FACS - results - 52% expression and 44% internalization. The variant showed a deleterious effect on the protein localization and function, and was associated with the accumulation of the protein in the ER. Results are below 70%, so PS3 is met. // Functional studies reported in PMID 21511053 (Zhao et al., 2011) performed using retrovirus transfected LDLR-/- fibroblasts, FACS and 125I-LDL assays - results - approximately 50% cell surface LDLR, 50-60% LDL-LDLR uptake and normal LDL-LDLR binding. Results are below 70%, so PS3 is met. -------- Overall, both functional studies are consistent with damaging effect. PS4, PP4: Variant meets PM2 and is identified in at least 17 unrelated index cases fulfilling criteria for FH (2 index cases from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; at least 15 cases from PMID 20538126, 22353362, 21376320, 25846081, 19318025). PP1_Strong: Variant segregates with FH phenotype in at least 9 informative meioses (minimum 6) from 3 families from different PMIDs (23155708, 2923363, 22353362): 9 affected family members have the variant. PM3: Variant meets PM2 and is identified in 1 index case (PMID 7903864) with homozygous FH phenotype and a deletion of LDLR exons 4-11, confirmed in trans, classified as Pathogenic by these guidelines; 1 index case (PMID 23155708) with homozygous FH phenotype and the LDLR c.2054C>T, p.(Pro685Leu) variant, confirmed in trans, classified as Pathogenic by these guidelines; 1 index case (PMID 29233637) with homozygous FH phenotype and the LDLR c.724C>T, p.(Gln242*) variant, confirmed in trans, classified as Pathogenic by these guidelines. -

Mar 30, 2017

U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2024

All of Us Research Program, National Institutes of Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Dec 16, 2016

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

Significance:Likely benign

Review Status:flagged submission

Collection Method:clinical testing

subject mutated among 2600 FH index cases screened = 1 /previously described in association with FH /Software predictions: Conflicting -

Dec 05, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:literature only

- -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation;literature only

- -

Jan 23, 2018

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Familial hypercholesterolemia

Pathogenic:6

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. This variant is also known as p.His562Tyr. ClinVar contains an entry for this variant (Variation ID: 200921). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Jul 18, 2024

Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method: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) -

Oct 12, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 16, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Feb 05, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Pathogenic:5

Clinical Genetics, Academic Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 13, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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) -

Jun 15, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Homozygous familial hypercholesterolemia

Pathogenic:2

Jan 02, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Dec 16, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Cardiovascular phenotype

Pathogenic:1

Jan 20, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.H583Y pathogenic mutation (also known as c.1747C>T and p.H562Y), located in coding exon 12 of the LDLR gene, results from a C to T substitution at nucleotide position 1747. The histidine at codon 583 is replaced by tyrosine, an amino acid with similar properties. This variant, which has been described as a Chinese founder mutation, was identified in one or more individuals with features consistent with familial hypercholesterolemia (FH) and segregated with disease in at least one family (Sun XM et al, Arterioscler. Thromb. 1994 Jan; 14(1):85-94; Yao RE et al, J. Pediatr. Endocrinol. Metab. 2012; 25(7-8):769-73; Chiou KR et al, Gene 2012 Apr; 498(1):100-6; Hooper AJ et al, Atherosclerosis 2012 Oct; 224(2):430-4; Fan LL et al, Appl. Biochem. Biotechnol. 2015 May; 176(1):101-9; Ma Y et al. J Clin Lipidol Oct;12:230-235.e6). This variant has been identified in the homozygous state and/or in conjunction with other LDLR variant(s) in individual(s) with features consistent with homozygous FH; in at least one instance, the variants were identified in trans (Chiou KR et al, Gene 2012 Apr; 498(1):100-6). Other variant(s) at the same codon, p.H583D (c.1747C>G), p.H583Q (c.1749C>A), have been identified in individual(s) with features consistent with FH (Bertolini S et al, Atherosclerosis 2013 Apr; 227(2):342-8; Alonso R et al, Clin. Biochem. 2009 Jun; 42(9):899-903). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;.;.;.;.;.

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.93

D;D;D;D;D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Pathogenic

3.3

M;.;.;.;.;M

PhyloP100

6.0

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-5.9

D;D;D;D;D;D

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.77

MutPred

0.86

Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);.;.;.;Gain of sheet (P = 0.0344);

MVP

1.0

MPC

0.87

ClinPred

0.45

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.99

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

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