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rs2228671

Variant summary

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

The NM_000527.5(LDLR):c.81C>A(p.Cys27Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. C27C) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

LDLR
NM_000527.5 stop_gained

Scores

2
1
4

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: -0.152
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. There are 2422 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-11100236-C-A is Pathogenic according to our data. Variant chr19-11100236-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 251009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11100236-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LDLRNM_000527.5 linkuse as main transcriptc.81C>A p.Cys27Ter stop_gained 2/18 ENST00000558518.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LDLRENST00000558518.6 linkuse as main transcriptc.81C>A p.Cys27Ter stop_gained 2/181 NM_000527.5 P3P01130-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4
Pathogenic, criteria provided, single submitterresearchFundacion Hipercolesterolemia FamiliarMar 01, 2016- -
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, 2016subjects mutated among 2600 FH index cases screened = 2 , family member = 1 with co-segregation -
Pathogenic, criteria provided, single submitterliterature onlyLDLR-LOVD, British Heart FoundationMar 25, 2016- -
Pathogenic, criteria provided, single submitterclinical testingU4M - Lille University & CHRU Lille, Université de Lille - CHRU de LilleMar 30, 2017ACMG Guidelines: Likely Pathogenic (ii) -
Familial hypercholesterolemia Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingInvitaeMar 27, 2023For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 251009). This variant is also known as C6X. This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 15556094, 23375686). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys27*) 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). -
Pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthAug 20, 2018Pathogenic variant based on current evidence: This variant changes a single nucleotide in exon 2 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 nor has this variant been reported in individuals affected with familial hypercholesterolemia in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Loss-of-function truncation variants in the LDLR gene are known to be pathogenic (PMID: 20809525). Based on available evidence, this variant is classified as Pathogenic. -
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJan 15, 2018The p.C27* pathogenic mutation (also known as c.81C>A), located in coding exon 2 of the LDLR gene, results from a C to A substitution at nucleotide position 81. This changes the amino acid from a cysteine to a stop codon within coding exon 2, and is located in the ligand-binding domain. This alteration has been reported in hypercholesterolemia cohorts (Laurie AD et al. Atheroscler Suppl, 2004 Dec;5:13-5; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8). 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
0.28
Cadd
Pathogenic
33
Dann
Uncertain
0.98
Eigen
Benign
-0.34
Eigen_PC
Benign
-0.68
FATHMM_MKL
Benign
0.36
N
MutationTaster
Benign
1.0
A;A;A;A;A;A;A
Vest4
0.80
GERP RS
-1.7
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: rs2228671; hg19: chr19-11210912; API