Genetic Variant LDLR:p.Arg350* (chr19-11110759-C-T) – ACMG Classification: Pathogenic (19 pts)

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:

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PVS1

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.

PP1

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

PP4

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LDLR	NM_000527.5	MANE Select	c.1048C>T	p.Arg350*	stop_gained	Exon 7 of 18	NP_000518.1
LDLR	NM_001195798.2		c.1048C>T	p.Arg350*	stop_gained	Exon 7 of 18	NP_001182727.1
LDLR	NM_001195799.2		c.925C>T	p.Arg309*	stop_gained	Exon 6 of 17	NP_001182728.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1048C>T	p.Arg350*	stop_gained	Exon 7 of 18	ENSP00000454071.1
LDLR	ENST00000252444.10	TSL:1	c.1306C>T	p.Arg436*	stop_gained	Exon 7 of 18	ENSP00000252444.6
LDLR	ENST00000558013.5	TSL:1	c.1048C>T	p.Arg350*	stop_gained	Exon 7 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000798

AC:

AN:

250716

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461026

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726822

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52800

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000809

AC:

AN:

1111816

Other (OTH)

AF:

0.00

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41442

American (AMR)

AF:

0.00

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

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:

2088

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

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:30

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:15

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:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

subjects mutated among 2600 FH index cases screened = 4 , family member = 3 with co-segregation / FH-Fossum

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

0/190 non-FH alleles; 0/100 healthy control individuals

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Jun 05, 2008

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

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 26, 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 10, 2022

North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria Codes: PP4 PM2 PP3 PS3_Supp PS4

Nov 05, 2016

Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 20, 2022

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:literature only

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Mar 25, 2022

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000527.5 (LDLR):c.1048C>T(p.Arg350Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PVS1, PP4, PS4, PP1_Strong) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: PopMax MAF = 0.00005 in East Asian population in gnomAD (gnomAD v2.1.1). PVS1: The variant causing a premature stop codon amino-terminal of amino acid 830 (NM_000527.5:p.Lys830). PP4: This variant meets PM2 and is identified in >1 index case who met clinical criteria for FH after alternative causes for high cholesterol were excluded. PS4: Variant meets PM2 and is identified in 23 unrelated index cases fulfil clinical criteria for FH. Ten cases fulfil Simon Broome FH criteria (5 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; 3 cases from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, PMID 22698793; 1 case from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge; 1 case from Division of Cardiology, Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan (PMID 20538126)). Thirteen cases fulfil DLCN criteria (10 cases from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA; 1 case each from Lipid Clinic, Fundación Jiménez Díaz, Madrid, Spain (PMID 19318025); Department of Genetics and Pathology, Pomeranian Medical Academy, Szczecin, Poland (PMID 9654205); GeneDx). PP1_Strong: Variant segregates with FH phenotype in 20 informative meiosis from at least 11 families. Fifteen affected relatives tested positive for the variant from at least 6 families from 4 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; Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation; GeneDx; Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA). Five unaffected relatives tested negative for the variant from 5 families (Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA).

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Pathogenic

Review Status:no assertion criteria provided

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

Jul 01, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 24, 2023

All of Us Research Program, National Institutes of Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant (also known as p.Arg329X and FH-Fossum) changes 1 nucleotide in exon 7 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional assays have not been performed for this variant. This variant been reported in numerous individuals affected with familial hypercholesterolemia (PMID: 7709162, 9039985, 21382890, 21310417, 22390909, 27680772, 28235710). It has also been reported in an individual affected with myocardial infarction (PMID: 25487149). This variant has been identified in 2/250716 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic.

Familial hypercholesterolemia

Pathogenic:6

Dec 11, 2023

GENinCode PLC

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1048C>T p.(Arg350Ter) variant in LDLR is a nonsense variant predicted to create a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been seen in >=10 FH patients meeting clinical criteria, including after alternative causes of high cholesterol were excluded (PS4_STRONG, PP4_SUPPORTING; PMIDs 7709162, 9039985, 9654205, 19318025, 20538126, 22698793 ClinGen FH VCEP data, internal data). It has been shown to segregate with disease in >=6 informative meioses in multiple families (PP1_STRONG; PMIDs 7709162, 9039985, ClinGen FH VCEP data) and has been seen in the compound heterozygous state with a second pathogenic variant in a patient with homozygous FH where parental testing confirmed variants were in trans (PM3_MODERATE; PMID 18263977). The highest population minor allele frequency in gnomAD v2.1. is 0.00005439 in East Asian population, which is lower than the ClinGen FH VCEP threshold (<0.0002) so PM2_MODERATE is met. Based on the evidence listed above, we have classified this variant as Pathogenic.

Dec 18, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg350*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with familial hypercholesterolemia and myocardial infarction (PMID: 7709162, 9039985, 20809525, 21310417, 21382890, 22390909, 25487149). 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 Arg329*. ClinVar contains an entry for this variant (Variation ID: 226342). For these reasons, this variant has been classified as Pathogenic.

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

May 26, 2020

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.1048C>T (p.Arg350X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 250716 control chromosomes (gnomAD). c.1048C>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Bertolini_2013, Humphries_2006, Solberg_1994, van der Graaf_2011). These data indicate that the variant is very likely to be associated with disease. Ten ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Sep 30, 2022

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant changes 1 nucleotide in exon 7 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as p.Arg329X and FH-Fossum in the literature. This variant been reported in numerous individuals affected with familial hypercholesterolemia (PMID: 7709162, 9039985, 21382890, 21310417, 22390909, 27680772, 28235710). It has also been reported in an individual affected with myocardial infarction (PMID: 25487149). This variant has been identified in 2/250716 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on available evidence, this variant is classified as Pathogenic.

not provided

Pathogenic:5

May 23, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as R329X and FH Fossum; This variant is associated with the following publications: (PMID: 7616128, 10208490, 21382890, 17765246, 25525159, 18263977, 25846081, 15256764, 17353666, 28502495, 19837725, 20145306, 20506408, 23054246, 25461735, 26875521, 22390909, 25487149, 7709162, 9654205, 19318025, 21310417, 23375686, 26415676, 27680772, 31727422, 28235710, 30592178, 32719484, 32522009, 33269076, 32770674, 32331935, 33740630, 33418990, 34037665, 33087929, 9039985, 26582918)

Feb 12, 2019

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 15, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Oct 01, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The LDLR c.1048C>T (p.Arg350*) variant (also known as R329X) causes the premature termination of LDLR protein synthesis. In the published literature, this variant has been reported in multiple individuals/families with familial hypercholesterolemia (PMIDs: 33994402 (2021), 25461735 (2015), 23375686 (2013), 21382890 (2011), 21310417 (2011), 20538126 (2010), 20145306 (2010), 19318025 (2009), 18263977 (2008), 17765246 (2008), 15256764 (2004), 9654205 (1998), 9039985 (1997), 7709162 (1994)), and early-onset myocardial infarction (PMID: 25487149 (2015)). The frequency of this variant in the general population, 0.000008 (2/250716 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.

Homozygous familial hypercholesterolemia

Pathogenic:1

Apr 05, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg350X variant in LDLR (also described as p.Arg329X in the literature) has been reported in >15 individuals with hypercholesterolemia and segregated with disease in >15 affected relatives from 8 families (Day 1997, Humphries 2006, Kubalska 2008, Dušková 2011, van der Graaf 2011, Tichý 2012, Huijgen 2012, Radovica-Spalvina 2015, Do 2015, Fan 2015). This variant has also been identified in 1/111552 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs769737896) and in ClinVar (Variation ID: 226342). This nonsense variant leads to a premature termination codon at position 350, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in individuals with familial hypercholesterolemia (FH). In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner. The ACMG/AMP Criteria applied: PVS1; PS4; PP1_Strong; PM2.

Hypercholesterolemia, autosomal dominant, type B

Pathogenic:1

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The stop gained p.R350* in LDLR (NM_000527.5) has been reported in numerous individuals and families affected with familial hypercholesterolemia (Solberg K et al; Day IN et al; Huijgen R et al). The variant has been reported to ClinVar as Pathogenic. The variant is expected to result in an absent or disrupted protein product. This variant is predicted to cause loss of normal protein function through protein truncation. Loss-of-function variants in LDLR are known to be pathogenic. For these reasons, this variant has been classified as Pathogenic.

See cases

Pathogenic:1

Jan 03, 2023

Institute of Human Genetics, University Hospital Muenster

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG categories: PVS1,PM2,PM5,PP3,PP5

Cardiovascular phenotype

Pathogenic:1

Jun 07, 2023

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R350* pathogenic mutation (also known as c.1048C>T), located in coding exon 7 of the LDLR gene, results from a C to T substitution at nucleotide position 1048. This changes the amino acid from an arginine to a stop codon within coding exon 7. This mutation (also known as p.R329* / FH Fossum) has been detected in multiple individuals with familial hypercholesterolemia (FH) from a range of ethnic backgrounds, with at least one compound heterozygote and co-segregation also reported (Solberg K et al. Scand. J. Clin. Lab. Invest., 1994 Dec;54:605-9; Day IN et al. J. Med. Genet., 1997 Feb;34:111-6; Kubalska J et al. J. Appl. Genet., 2008;49:109-13; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Martin R et al. Atherosclerosis, 2016 11;254:8-13). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.37

Eigen_PC

Benign

0.073

FATHMM_MKL

Uncertain

0.94

PhyloP100

2.4

Vest4

0.92

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=0/200

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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19-11110759-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over