rs199774121

Variant summary

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

The ENST00000558518.6(LDLR):​c.429C>A​(p.Cys143Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,586 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

LDLR
ENST00000558518.6 stop_gained

Scores

2
3
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 0.243
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 19-11105335-C-A is Pathogenic according to our data. Variant chr19-11105335-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 226325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105335-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LDLRNM_000527.5 linkuse as main transcriptc.429C>A p.Cys143Ter stop_gained 4/18 ENST00000558518.6 NP_000518.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LDLRENST00000558518.6 linkuse as main transcriptc.429C>A p.Cys143Ter stop_gained 4/181 NM_000527.5 ENSP00000454071 P3P01130-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251178
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135822
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:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461586
Hom.:
0
Cov.:
33
AF XY:
0.00000825
AC XY:
6
AN XY:
727118
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000809
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:9
Pathogenic, criteria provided, single submitterclinical testingU4M - Lille University & CHRU Lille, Université de Lille - CHRU de LilleMar 30, 2017- -
Pathogenic, criteria provided, single submitterliterature onlyLDLR-LOVD, British Heart FoundationMar 25, 2016- -
Pathogenic, no assertion criteria providedresearchLaboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum-- -
Pathogenic, criteria provided, single submitterresearchFundacion Hipercolesterolemia FamiliarMar 01, 2016- -
Pathogenic, no assertion criteria providedclinical testingCardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley HospitalFeb 18, 2016- -
Pathogenic, criteria provided, single submitterclinical testingDepartment of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und KollegenMay 08, 2018This nonsense mutation leads to a complete loss of the receptor function. In addition, the variant was observed in multiple studies in patients with FH. In our case the mutation was observed in a patient with TC up to 550 mg/dl at the age of 35. PMID: 9212177, 25487149 -
Pathogenic, no assertion criteria providedclinical testingClinical Genomics Laboratory, Stanford MedicineDec 31, 2020The p.Cys143* variant in the LDLR gene has been previously reported in at least 22 unrelated individuals with familial hypercholesterolemia (Descamps et al., 1997; Ekström et al., 1998; Lombardi et al., 1998; Jensen et al., 1999; Amsellem et al., 2002; van der Graaf et al., 2011; Natarajan et al., 2016), and one paper reported that it co-segregated with known or suspected FH in 71 relatives from 11 unrelated families (Descamps et al., 1997). This variant is also known as p.Cys122* in the literature. The p.Cys143* variant has been identified in 2/113,608 European (non-Finnish) chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant leads to a premature stop codon in exon 4 of 18 coding exons, and is therefore predicted to undergo nonsensemediated decay resulting in a truncated or absent protein. Heterozygous loss of function is an established mechanism of disease for the LDLR gene. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Cys143* variant as pathogenic for autosomal dominant familial hypercholesterolemia based on the information above. [ACMG evidence codes used: PVS1; PS4; PM2] -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterMar 05, 2024Criteria applied: PVS1,PS4,PM2_SUP -
Pathogenic, criteria provided, single submitterclinical testingCentre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-FoixDec 16, 2016- -
not provided Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoDec 03, 2020This nonsense variant causes the premature termination of LDLR protein synthesis. It has been reported in individuals affected with familial hypercholesteremia in the published literature (PMID: 9767373 (1998), 9452078 (1998), 27831900 (2016), 21382890 (2011), 19318025 (2009)). Therefore, the variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenSep 08, 2022PVS1, PS4, PP3 -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics Laboratory, Skane University Hospital LundNov 06, 2023- -
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsNov 01, 2019The p.C143* pathogenic mutation (also known as c.429C>A), located in coding exon 4 of the LDLR gene, results from a C to A substitution at nucleotide position 429. This changes the amino acid from a cysteine to a stop codon within coding exon 4. This alteration has been reported in multiple subjects with familial hypercholesterolemia (FH) (Descamps O et al. Clin. Genet., 1997 May;51:303-8; Lombardi P et al. Hum. Mutat., 1998;Suppl 1:S172-4; Amsellem S et al. Hum. Genet., 2002 Dec;111:501-10; van der Graaf A et al. Circulation, 2011 Mar;123:1167-73). 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. -
Familial hypercholesterolemia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 17, 2023This sequence change creates a premature translational stop signal (p.Cys143*) 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 (rs199774121, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 9212177, 16542394, 21382890, 27831900). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys122*. ClinVar contains an entry for this variant (Variation ID: 226325). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.50
CADD
Pathogenic
33
DANN
Uncertain
0.99
Eigen
Uncertain
0.22
Eigen_PC
Benign
-0.042
FATHMM_MKL
Uncertain
0.96
D
MutationTaster
Benign
1.0
A;A;A;A;D;D;D
Vest4
0.84
GERP RS
1.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.13
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: rs199774121; hg19: chr19-11216011; API