19-11113420-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS4PP1_StrongPM2PP3PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1329G>C (p.Trp443Cys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PP1_Strong, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 31 January 2025.The supporting evidence is as follows: PM2: PopMax MAF = 0.0000007200 (0.00007200%) in European (non-Finnish) exomes (gnomAD v4.1.0).PP3: REVEL = 0.961.PS4, PP4: Variant meets PM2 and is identified in at least 14 unrelated index cases who fulfill FH criteria from different labs (5 cases with DLCN score >=6 and 5 cases with possible FH by Simon Broome criteria 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; 2 cases with DLCN score >=6 and 2 cases with possible FH by Simon Broome criteria from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France). PP1_Strong: Variant segregates with FH phenotype in at least 6 informative meioses from 5 families from different labs (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France): 6 affected family members have the variant. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585409/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:19

Conservation

PhyloP100: 9.88

Publications

8 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 links:

MIR6886 (HGNC:50121): (microRNA 6886) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR6886 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PS4

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

PM2

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.1329G>C	p.Trp443Cys	missense_variant	Exon 9 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.1329G>C	p.Trp443Cys	missense_variant	Exon 9 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152158

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461678

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53214

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:10

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

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 pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

subjects mutated among 2600 FH index cases screened = 10 , family members = 5 with co-segregation / previously described in association with FH / Software predictions: Damaging

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:literature only

Jan 10, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 19, 2020

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1329G>C (p.Trp443Cys) variant in the LDLR gene results in an amino acid change at residue 443 from a tryptophan to a cysteine. This variant has been reported in multiple unrelated individuals and families with familial hypercholesterolemia (PMID: 1301956, 11196104, 9664576, 9727746, 22390909). It has not been observed in the population database (gnomAD). It is located within the functionally important LDL-receptor class B repeat 2 region of the encoded protein. Multiple lines of in silico algorithms predicts this p.Trp443Cys change to be deleterious. A different nucleotide change at the same position (c.1329G>T) resulting in the same amino acid change (p.Trp443Cys) is considered pathogenic. Another variant that changes the residue 443 from tryptophan to arginine has been reported as pathogenic (PMID: 28290784 and 28458923). Therefore, this variant c.1329G>C (p.Trp443Cys) in LDLR is interpreted as pathogenic.

Jan 31, 2025

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000527.5(LDLR):c.1329G>C (p.Trp443Cys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PP1_Strong, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 31 January 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.0000007200 (0.00007200%) in European (non-Finnish) exomes (gnomAD v4.1.0). PP3: REVEL = 0.961. PS4, PP4: Variant meets PM2 and is identified in at least 14 unrelated index cases who fulfill FH criteria from different labs (5 cases with DLCN score >=6 and 5 cases with possible FH by Simon Broome criteria 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; 2 cases with DLCN score >=6 and 2 cases with possible FH by Simon Broome criteria from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France). PP1_Strong: Variant segregates with FH phenotype in at least 6 informative meioses from 5 families from different labs (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France): 6 affected family members have the variant.

May 27, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PS1,PS3_MOD,PS4,PM5_STR,PM2_MOD,PP3, PP1

Jul 07, 2023

All of Us Research Program, National Institutes of Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 08, 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

not provided

Pathogenic:4

Dec 30, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3_moderate, PS4_moderate, PM2_supporting, PP3

Jun 05, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not found in the total gnomAD dataset, and the data is high quality (0/282626 chr). Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Multiple pathogenic or likely pathogenic variants affect the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function.

Jan 27, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published in vivo analysis suggest a statistically significant elevation of LDL-C levels in patients with W443C compared to wild type patients (PMID: 22390909); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as W422C and FH North Platt; This variant is associated with the following publications: (PMID: 31447099, 32220565, 9664576, 1301956, 9727746, 11810272, 21382890, 11845603, 11196104, 12436241, 33111339, 34037665, 34363016, 32770674, 23833242, 33740630, 22390909)

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LDLR: PM1:Strong, PS1, PM2, PS4:Supporting

Familial hypercholesterolemia

Pathogenic:3

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 443 of the LDLR protein (p.Trp443Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypercholesterolemia (PMID: 1301956, 9664576, 9727746, 11196104, 22390909). 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.Trp422Cys. ClinVar contains an entry for this variant (Variation ID: 251792). 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%. This variant disrupts the p.Trp443 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 28458923), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Mar 29, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant (also known as p.Trp422Cys in the mature protein) replaces tryptophan with cysteine at codon 443 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that human cells compound heterozygous for this variant and p.Pro685Leu show 5-15% LDLR activity (PMID: 1301956). This variant has been reported in over 90 individuals affected with familial hypercholesterolemia (PMID: 1301956, 11196104, 9664576, 9727746, 22390909, 33740630). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

Apr 05, 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.1329G>C (p.Trp443Cys) results in a non-conservative amino acid change located in the LDLR class B repeat (IPR000033) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251246 control chromosomes (gnomAD). c.1329G>C has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Weiss_2000, Kusters_2013, Leren_2021). These data indicate that the variant is very likely to be associated with disease. Twelve ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Homozygous familial hypercholesterolemia

Pathogenic:1

Jan 31, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Trp443Cys variant in LDLR has been reported in >90 individuals with famili al hypercholesterolemia (FH) and was absent from large population studies. In vi tro functional studies demonstrate that this variant results in reduced protein activity (Hobbs 1992). Computational prediction tools and conservation analysis suggest that the p.Trp443Cys variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dom inant manner based upon prevalence among probands, absence from controls, and fu nctional evidence.

Cardiovascular phenotype

Pathogenic:1

Aug 08, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1329G>C (p.W443C) alteration is located in exon 9 (coding exon 9) of the LDLR gene. This alteration results from a G to C substitution at nucleotide position 1329, causing the tryptophan (W) at amino acid position 443 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant (also referred to as p.W422C and North Platt) has been detected in numerous individuals with familial hypercholesterolemia (FH) from a variety of ethnic backgrounds (Hobbs, 1992; Fouchier, 2001; Vergotine, 2001; van der Graaf, 2011). A different nucleotide substitution resulting in the same amino acid change (c.1329G>T) has also been detected in individuals with FH (Huijgen, 2012). Other variants at the same codon, p.W443R (c.1327T>C) and p.W443S (c.1328G>C), have also been reported in association with FH (Sozen, 2004; Korneva, 2017). This amino acid position is highly conserved in available vertebrate species. Internal structural analysis indicates that this variant, which impacts a conserved residue in the YWTD motif of an LDLR class B repeat, is structurally disruptive (Lo Surdo, 2011; Ambry internal data). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.61

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.98

D;.;.;.;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D;D;D;D

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

1.0

D;D;D;D;D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

4.2

H;.;.;.;.;H

PhyloP100

9.9

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-13

D;D;D;D;D;D

REVEL

Benign

0.0

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Vest4

0.88

ClinPred

1.0

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

1.0

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over