19-11105425-C-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000527.5(LDLR):c.519C>G(p.Cys173Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C173S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: -0.169

Publications

11 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 19 ACMG points.

PM1

In a hotspot region, there are 40 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000527.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-11105424-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 689345.Status of the report is no_assertion_criteria_provided, 0 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 678 curated pathogenic missense variants (we use a threshold of 10). The gene has 92 curated benign missense variants. Gene score misZ: 0.12407 (below the threshold of 3.09). Trascript score misZ: 0.59338 (below the threshold of 3.09). GenCC associations: The gene is linked to hypercholesterolemia, familial, 1, homozygous familial hypercholesterolemia.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 19-11105425-C-G is Pathogenic according to our data. Variant chr19-11105425-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 251277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.519C>G	p.Cys173Trp	missense_variant	Exon 4 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.519C>G	p.Cys173Trp	missense_variant	Exon 4 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251308

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461740

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727178

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:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53288

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111994

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:6

May 14, 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 cysteine with tryptophan at codon 173 in the LDLR type A repeat 4 in the ligand binding domain of the LDLR protein. This variant is also known as p.Cys152Trp in the mature protein. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Functional studies have shown that this variant results in a significant decrease in LDL binding and internalization (PMID: 9544726, 16502360). This variant has been reported in over 10 unrelated individuals affected with familial hypercholesterolemia (PMID: 11462246, 11810272, 25962062, 31345425, 32044282, 32220565, 33418990, 34037665, 34182004, 34456200, 37119068). It has been shown that this variant segregates with hypercholesterolemia in over 10 individuals from two unrelated families (PMID: 9452094, 9544726). This variant has been identified in 2/251308 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Cys173Arg), is considered to be disease-causing (ClinVar variation ID: 251272), suggesting that cysteine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. -

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

- -

Robarts Research Institute, Western University

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 11, 2019

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:literature only

- -

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

not provided

Pathogenic:3

Jul 28, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. Segregation with disease in affected and unaffected individuals from a single family. -

Jan 30, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect through abnormal ligand binding and receptor internalization (Plewa et al., 2006); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as C152W; This variant is associated with the following publications: (PMID: 9452094, 10090484, 11810272, 26343872, 9544726, 34456200, 32044282, 11462246, 25962062, 34037665, 28619117, 16502360, 33418990, 34182004, 34875256) -

Jul 24, 2015

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:provider interpretation

The patient had genetic testing for the familial hypercholesterolemia panel. The test included sequencing of three genes associated with familial hypercholesterolemia: LDLR, APOB and PCSK9. Results showed that the following variant was identified: - p.C173W (c.519C>G) in the LDLR gene. The lab classifies this as a pathogenic mutation. Given sufficient case data and it's disruption of the binding site of the low density lipoprotein receptor protein we consider this variant likely pathogenic and we feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least five unrelated cases of familial hypercholesterolemia (not including this patient's family). There is two generation segregation data presented in one family with four affected individuals. Couture, et al., 1998 reported a novel variant p.C173W (reported as p.C152W and c.519C>G in the paper). The C-to-G transversion at nucleotide 519 results in a change in the highly conserved cysteine at the C-terminal end in the fourth of the seven tandem cysteine repeats that for the binding site for LDLR (Bieri et al., 1995; Mehta et al., 1991). They variant segregated with FH in four individuals who had LDLs of 178, 298, 200 and 263, three of whom had tendinous xanthomas and two of which had coronary artery disease. Ebhardt, et al., 1999 reported a patient with p.C173W (reported as p.C152W and c.519C>G in the paper) in a Northern German individual that segregated with FH in the family (no details on number of individuals). Fouchier, et al., 2001; Morash, et al., 1998; Nauck, et al., 1997 all reported a patient with p.C173W (reported as p.C152W). The do not offer clinical details other than each patient had a diagnosis of familial hypercholesterolemia. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar: 1.00) and Mutation Taster predicts that it's disease causing (0.999). The cysteine at codon 173 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (C152R in a greek patient with compound heterozygous FH) and nearby codons (167, 175, and 177 in clinvar). In total the variant has not been seen in 100 published controls and individuals from publicly available population datasets. There is no missense variation at codon 173 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of July 24, 2015). There were 16,512 individuals of South Asian descent. -

Familial hypercholesterolemia

Pathogenic:3

Sep 08, 2021

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.519C>G (p.Cys173Trp) results in a non-conservative amino acid change located in the Low-density lipoprotein (LDL) receptor class A repeat (IPR002172) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251308 control chromosomes (gnomAD). c.519C>G has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia and has been shown to segregate with disease in several affected individuals within two unrelated families (e.g. Couture_1998, Morash_1998, Ebhardt_1999, Fouchier_2001, Nauck_2001, Plewa_2006). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant results in a significant decrease in LDL binding capacity (Morash_1998, Plewa_2006). Eight ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 14, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 173 of the LDLR protein (p.Cys173Trp). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9452094, 11462246, 11810272, 25962062). It has also been observed to segregate with disease in related individuals. 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.Cys152Trp. ClinVar contains an entry for this variant (Variation ID: 251277). 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.Cys173 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7489239, 20019594). 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. -

Dyslipidemia

Pathogenic:1

Oct 16, 2024

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3_supp;PS4;PM5_strong;PM1;PM2;PP1_strong;PP3 -

Cardiovascular phenotype

Pathogenic:1

Feb 08, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.C173W pathogenic mutation (also known as c.519C>G), located in coding exon 4 of the LDLR gene, results from a C to G substitution at nucleotide position 519. The cysteine at codon 173 is replaced by tryptophan, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). This mutation, which is also known as p.C152W, has been reported in multiple individuals with FH and was observed to segregate with elevated LDL-levels across two generations in one family (Couture P et al. Hum Mutat, 1998;Suppl 1:S226-31; Morash BA et al. Atherosclerosis, 1998 Jan;136:9-16; Ebhardt M et al. Hum Mutat, 1999;13:257; Fouchier SW et al. Hum Genet, 2001 Dec;109:602-15; Nauck MS et al. Hum Mutat, 2001 Aug;18:165-6; Shin DG et al. Atherosclerosis, 2015 Nov;243:53-8; Meshkov A et al. Genes (Basel), 2021 01;12:[ePub ahead of print]; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 4 (Ambry internal data). This alteration is predicted to be deleterious by BayesDel 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

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.47

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.98

D;.;.;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.59

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Pathogenic

4.4

H;.;.;H

PhyloP100

-0.17

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-10

D;D;D;D

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.96

MutPred

0.93

Loss of disorder (P = 0.0414);Loss of disorder (P = 0.0414);.;Loss of disorder (P = 0.0414);

MVP

1.0

MPC

0.95

ClinPred

1.0

GERP RS

-3.7

PromoterAI

-0.015

Neutral

(source)

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