19-11120425-C-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000527.5(LDLR):​c.2043C>A​(p.Cys681*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,784 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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

LDLR
NM_000527.5 stop_gained

Scores

2
2
3

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:34

Conservation

PhyloP100: -0.847
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-11120425-C-A is Pathogenic according to our data. Variant chr19-11120425-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120425-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LDLRNM_000527.5 linkc.2043C>A p.Cys681* stop_gained Exon 14 of 18 ENST00000558518.6 NP_000518.1 P01130-1A0A024R7D5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LDLRENST00000558518.6 linkc.2043C>A p.Cys681* stop_gained Exon 14 of 18 1 NM_000527.5 ENSP00000454071.1 P01130-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251278
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135852
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000684
AC:
10
AN:
1461784
Hom.:
0
Cov.:
35
AF XY:
0.00000688
AC XY:
5
AN XY:
727210
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:34
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:21
Sep 02, 2022
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial hypercholesterolaemia, 1 (MIM#143890). (I) 0108 - This gene is associated with both recessive and dominant disease. Variants have been reported in heterozygous, compound heterozygous and homozygous state with the recessive disease being more severe (OMIM, PMID: 10978268). (I) 0112 - The condition associated with this gene has incomplete penetrance (GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic, and observed in individuals with familial hypercholesterolaemia (Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has been observed in both heterozygous and homozygous state in individuals with familial hypercholesterolaemia. It is regarded as a founder variant within the Lebanese population (ClinVar). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 01, 2016
Iberoamerican FH Network
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Aug 21, 2023
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PVS1, PM2, PP5 - It's pathogenicity has already been established. ClinVar Variation ID 3699. -

Nov 05, 2016
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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

- -

-
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 09, 2018
Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The nucleotide substitution c.2043C> A leads to a premature termination of protein synthesis at position 681 and is described as "FH Lebanese allele" in the literature. The mutation leads to intracellular degradation of the LDL receptor and loss of function. The mutation described here has also been described in patients with hypercholesterolemia and is therefore classified as pathogenic. PMID: 1453433, 3025214 -

Dec 18, 2023
All of Us Research Program, National Institutes of Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant changes 1 nucleotide in exon 14 of the LDLR gene, creating a premature translation stop signal. This variant is also known as p.Cys660* in the mature protein. This variant is expected to result in an absent or non-functional protein product. Functional studies have shown that this variant causes a significant decrease in LDLR expression and LDL uptake (PMID: 31578082). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 3025214, 11668627, 19319977, 21145767, 25461735, 28502510, 28761763, 28873201, 31578082, 34321884) and is considered to be a founder variant in the Lebanese population (PMID: 19319977). This variant has also been observed in both homozygous and compound heterozygous state with a known pathogenic LDLR variant in multiple individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 28761763, 31578082). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 19319977, 34321884). This variant has been identified in 2/251278 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 the available evidence, this variant is classified as Pathogenic. -

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

- -

Nov 21, 2023
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Criteria applied: PVS1,PS4,PM2_SUP,PP1 -

Nov 01, 1991
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Nov 02, 2015
Blueprint Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 01, 2016
Fundacion Hipercolesterolemia Familiar
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Mar 25, 2016
LDLR-LOVD, British Heart Foundation
Significance: 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

- -

Nov 14, 2022
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 01, 2016
Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

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 = 31 (1 homozygote) , family members = 17 with co-segregation / FH-Libanon, < 2% LDLR Activity -

-
Robarts Research Institute, Western University
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 04, 2012
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Pathogenic:5
Mar 06, 2023
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This nonsense variant causes the premature termination of LDLR protein synthesis. The frequency of this variant in the general population, 0.000008 (2/251278 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported as a Lebanese founder mutation, but has also been identified in multiple other ethnic groups, in individuals and families with familial hypercholesterolemia (PMID: 28873201 (2017), 25461735 (2015), 22487947 (2012), 21145767 (2011), 19319977 (2009), 14974088 (2004), 11668627 (2001), 9664576 (1998), 3025214 (1987)). In a functional study, this variant was found to have a damaging effect on LDLR expression and binding (PMID: 31578082 (2019)). Based on the available information, this variant is classified as pathogenic. -

May 04, 2023
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP1, PS3, PS4_moderate, PVS1 -

Sep 16, 2018
Gharavi Laboratory, Columbia University
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Jul 13, 2022
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 08, 2024
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; Reported many times in the heterozygous, compound heterozygous, and homozygous states in individuals with FH (PMID: 9664576, 9259195, 3025214, 10737984, 11668627, 12406975, 15200491, 28873201, 30179711); Considered a Lebanese founder mutation and may account for greater than 80% of FH cases in this population (PMID: 19319977); Published functional studies suggest a damaging effect on protein expression and binding (PMID: 31578082); Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(C660X); This variant is associated with the following publications: (PMID: 31447099, 22487947, 25487149, 25525159, 3025214, 9259195, 9664576, 10737984, 11668627, 12406975, 15200491, 28873201, 30179711, 29407885, 34040191, 33303402, 34037665, 32041611, 33740630, 32770674, 33418990, 32231684, 35379577, 32009526, 33955087, 34321884, 15321837, 19319977, 37128917, 31578082) -

Familial hypercholesterolemia Pathogenic:5
Feb 02, 2025
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.Cys681*) 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). This variant is present in population databases (rs121908031, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 1959928, 11668627, 19319977, 21145767, 22487947, 25461735). 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.Cys660*. ClinVar contains an entry for this variant (Variation ID: 3699). For these reasons, this variant has been classified as Pathogenic. -

Jul 31, 2018
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2043C>A (p.Cys681*) variant in the LDLR gene has been reported in multiple individual patients with familial Hypercholesterolemia and segregated in the families (PMID: 3025214, 1959928, 1453433, 12406975, 22487947). This variant is extremely rare in general population and is predicted to introduce a premature translation termination codon. Therefore, the c.2043C>A (p.Cys681*) variant in the LDLR gene is classified as pathogenic. -

Aug 17, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Oct 19, 2023
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 14 of the LDLR gene, creating a premature translation stop signal. This variant is also known as p.Cys660* in the mature protein. This variant is expected to result in an absent or non-functional protein product. Functional studies have shown that this variant causes a significant decrease in LDLR expression and LDL uptake (PMID: 31578082). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 3025214, 11668627, 19319977, 21145767, 25461735, 28502510, 28761763, 28873201, 31578082, 34321884) and is considered to be a founder variant in the Lebanese population (PMID: 19319977). This variant has also been observed in both homozygous and compound heterozygous state with a known pathogenic LDLR variant in multiple individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 28761763, 31578082). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 19319977, 34321884). This variant has been identified in 2/251278 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 the available evidence, this variant is classified as Pathogenic. -

Oct 26, 2016
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: The LDLR c.2043C>A (p.Cys681X) variant results in a premature termination codon, predicted to cause a truncated or absent LDLR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified in the pathogenic spectrum by our laboratory (e.g. p.Trp813X, p.Ser710fsX2 ). Mutation taster predicts a damaging outcome for this variant. This variant was found in 1/121136 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0025031). It was observed in several FH families and showed co-segregation with the disease indicating causality. Moreover, the variant was shown to result in lack of detectable high affinity binding and uptake of LDL, further supporting pathogenicity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Homozygous familial hypercholesterolemia Pathogenic:1
Feb 22, 2021
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Cys681X variant in LDLR has been reported in >80 individuals with hypercholesterolemia across several studies and segregated with disease in >10 affected relatives (Abifadel 2009, Banares 2017, Fahed 2011, Jannes 2015, Lehrman 1987, Tichy 2012, Vandrovcova 2013). This variant is considered to be a founder variant in the Lebanese population (Fahed 2016). This variant has also been reported in Clinvar (Variation ID 3699) and has been identified in 1/113666 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 681, 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 familial hypercholesterolemia (FH). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP criteria applied: PVS1, PS4, PM2, PP1_Strong. -

See cases Pathogenic:1
Mar 04, 2021
Institute of Human Genetics, University Hospital Muenster
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG categories: PVS1,PM2,PP1,PP5 -

Cardiovascular phenotype Pathogenic:1
Aug 29, 2022
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2043C>A (p.C681*) alteration, located in exon 14 (coding exon 14) of the LDLR gene, consists of a C to A substitution at nucleotide position 2043. This changes the amino acid from a cysteine (C) to a stop codon at amino acid position 681. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration, also noted as p.C660X or the Lebanese allele, has been reported in individuals with familial hypercholesterolemia and a founder effect was proposed (Lehrman, 1987; Abifadel, 2009; Fahed, 2012). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
34
DANN
Uncertain
0.98
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.58
FATHMM_MKL
Uncertain
0.91
D
Vest4
0.94
GERP RS
-4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121908031; hg19: chr19-11231101; API