19-11110759-C-T

Position:

• chr19-11110759-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PS4 PP1_Strong PM2 PVS1 PP4

This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA031387/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: LDLR NM_000527.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:28
• Conservation: PhyloP100: 2.42

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.1048C>T	p.Arg350Ter	stop_gained	7/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.1048C>T	p.Arg350Ter	stop_gained	7/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250716 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135606

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461026 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726822

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:28

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:15

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Jun 05, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	subjects mutated among 2600 FH index cases screened = 4 , family member = 3 with co-segregation / FH-Fossum -
Pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Mar 25, 2022	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). -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jan 20, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 24, 2023	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. -
Pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Jan 26, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 01, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/190 non-FH alleles; 0/100 healthy control individuals -
Pathogenic, criteria provided, single submitter	clinical testing	North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust	Mar 10, 2022	Criteria Codes: PP4 PM2 PP3 PS3_Supp PS4 -
Pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Sep 15, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 05, 2019	This variant causes the premature termination of LDLR protein synthesis. It has been reported in multiple individuals and families with familial hypercholesterolemia and/or early myocardial infarction in the published literature (PMIDs: 25487149 (2015), 25461735 (2015), 23375686 (2013), 21382890 (2011), 21310417 (2011), 20538126 (2010), and 7709162 (1994)). -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Feb 12, 2019	- -

Familial hypercholesterolemia Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 03, 2023	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). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 30, 2022	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. -
Pathogenic, criteria provided, single submitter	research	Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 26, 2020	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. -

Homozygous familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 05, 2019

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

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

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

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Jan 03, 2023

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

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2023

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.37
Eigen_PC	Benign	0.073
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
Vest4		0.92
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs769737896; hg19: chr19-11221435;