chr19-11089587-C-CT
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000527.5(LDLR):c.41dupT(p.Leu14PhefsTer38) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,406 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
LDLR
NM_000527.5 frameshift
NM_000527.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.258
Publications
3 publications found
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]
LDLR-AS1 (HGNC:54407): (LDLR antisense RNA 1) This gene represents a regulatory lncRNA that overlaps the 5' UTR and coding sequence of the LDLR (low density lipoprotein receptor) gene. This lncRNA overlaps LDLR in the antisense orientation, and has been shown to downregulate production of the low density lipoprotein receptor. [provided by RefSeq, Jul 2019]
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 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 1827 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-11089587-C-CT is Pathogenic according to our data. Variant chr19-11089587-C-CT is described in ClinVar as Pathogenic. ClinVar VariationId is 250979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| LDLR | MANE Select | c.41dupT | p.Leu14PhefsTer38 | frameshift | Exon 1 of 18 | NP_000518.1 | P01130-1 | ||
| LDLR | c.41dupT | p.Leu14PhefsTer38 | frameshift | Exon 1 of 18 | NP_001182727.1 | P01130-5 | |||
| LDLR | c.41dupT | p.Leu14PhefsTer38 | frameshift | Exon 1 of 17 | NP_001182728.1 | P01130-4 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| LDLR | TSL:1 MANE Select | c.41dupT | p.Leu14PhefsTer38 | frameshift | Exon 1 of 18 | ENSP00000454071.1 | P01130-1 | ||
| LDLR | TSL:1 | c.41dupT | p.Leu14PhefsTer38 | frameshift | Exon 1 of 18 | ENSP00000453346.1 | P01130-5 | ||
| LDLR | TSL:5 | c.41dupT | p.Leu14PhefsTer38 | frameshift | Exon 1 of 18 | ENSP00000453557.1 | H0YMD1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460406Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726458 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1460406
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
726458
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33454
American (AMR)
AF:
AC:
0
AN:
44696
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26112
East Asian (EAS)
AF:
AC:
0
AN:
39700
South Asian (SAS)
AF:
AC:
0
AN:
86162
European-Finnish (FIN)
AF:
AC:
0
AN:
52970
Middle Eastern (MID)
AF:
AC:
0
AN:
5146
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1111890
Other (OTH)
AF:
AC:
1
AN:
60276
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
3
-
-
Hypercholesterolemia, familial, 1 (3)
1
-
-
Cardiovascular phenotype (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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