rs756039188
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000527.5(LDLR):c.12G>A(p.Trp4Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,160 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 (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
LDLR
NM_000527.5 stop_gained
NM_000527.5 stop_gained
Scores
2
1
4
Clinical Significance
Conservation
PhyloP100: -0.906
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. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 1041 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-11089560-G-A is Pathogenic according to our data. Variant chr19-11089560-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 237860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11089560-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.12G>A | p.Trp4Ter | stop_gained | 1/18 | ENST00000558518.6 | NP_000518.1 | |
LDLR-AS1 | NR_163945.1 | n.100C>T | non_coding_transcript_exon_variant | 1/1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.12G>A | p.Trp4Ter | stop_gained | 1/18 | 1 | NM_000527.5 | ENSP00000454071 | P3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248706Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135102
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460160Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726388
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:6
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The p.Trp4Ter (sometimes called p.Trp-18Ter) variant in LDLR has been reported in 53 individuals (including including 48 Spanish, 3 Chinese, and 2 Mexican individuals) with Familial Hypercholesterolemia, segregated with disease in 3 affected relatives from 1 family (PMID: 7903864, 20428891, 21868016, 1301956, 16314194), and has been identified in 0.002897% (1/34516) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs756039188). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported pathogenic in ClinVar (Variation ID: 237860). This nonsense variant leads to a premature termination codon at position 4, 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. One pathogenic variant with the same amino acid change as this variant has been reported in association with Familial Hypercholesterolemia in ClinVar, supporting that this variant may be pathogenic (Variation ID: 250973). In summary, this variant meets criteria to be classified as pathogenic for Familial Hypercholesterolemia in an autosomal dominant manner based on the predicted impact of the variant and multiple occurrences in individuals with Familial Hypercholesterolemia. ACMG/AMP Criteria applied: PVS1, PS1, PS4, PP1 (Richards 2015). - |
Pathogenic, criteria provided, single submitter | research | Iberoamerican FH Network | Mar 01, 2016 | - - |
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 | ACMG Guidelines: Pathogenic (i) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 29, 2019 | - - |
Pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Familial hypercholesterolemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 06, 2023 | This sequence change creates a premature translational stop signal (p.Trp4*) 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 (rs756039188, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 7903864, 16314194, 20428891, 21376320, 21868016). ClinVar contains an entry for this variant (Variation ID: 237860). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A;A;A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at