rs121908031

chr19-11120425-C-Achr19-11120425-C-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000527.5(LDLR):c.2043C>A(p.Cys681Ter) 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:31
• Conservation: PhyloP100: -0.847

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 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/exons	MANE	UniProt
LDLR	NM_000527.5	c.2043C>A	p.Cys681Ter	stop_gained	14/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.2043C>A	p.Cys681Ter	stop_gained	14/18	1	NM_000527.5	P3

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

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

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:31

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:19

Pathogenic, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	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. -
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 = 31 (1 homozygote) , family members = 17 with co-segregation / FH-Libanon, < 2% LDLR Activity -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 14, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	Aug 09, 2018	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 -
Pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	May 11, 2019	- -
Pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 21, 2023	Criteria applied: PVS1,PS4,PM2_SUP,PP1 -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	May 04, 2012	- -
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	literature only	OMIM	Nov 01, 1991	- -

Familial hypercholesterolemia Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 26, 2016	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 17, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	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. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 19, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jul 31, 2018	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. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 06, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 24, 2021	Considered a Lebanese founder mutation and may account for greater than 80% of FH cases in this population (Abifadel et al., 2009); Also known as p.(C660X); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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; Published functional studies suggest a damaging effect on protein expression and binding (Banerjee et al., 2019); Located in the middle of a cysteine-rich sequence that is part of the epidermal growth factor precursor homology domain; Reported in ClinVar (ClinVar Variant ID# 3699; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31447099, 22487947, 25487149, 25525159, 3025214, 9259195, 9664576, 10737984, 11668627, 12406975, 15200491, 19319977, 28873201, 30179711, 29407885, 33303402, 34037665, 32041611, 33740630, 32770674, 33418990, 32231684, 31578082, 15321837) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 04, 2023	PP1, PS3, PS4_moderate, PVS1 -

Homozygous familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 22, 2021

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. -

Hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Mar 04, 2021

ACMG categories: PVS1,PM2,PP1,PP5 -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 29, 2022

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
MutationTaster	Benign	1.0	A;A;A;A;A;A;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

Other links and lift over

dbSNP: rs121908031; hg19: chr19-11231101;