rs1555808118
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000527.5(LDLR):c.2259dupT(p.Gly754TrpfsTer28) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G754G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
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: -1.54
Publications
0 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 Gene-Disease associations (from GenCC):
- hypercholesterolemia, familial, 1Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
- homozygous familial hypercholesterolemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 12 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 19-11123291-C-CT is Pathogenic according to our data. Variant chr19-11123291-C-CT is described in ClinVar as Pathogenic. ClinVar VariationId is 440686.Status of the report is criteria_provided_single_submitter, 1 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
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | MANE Select | c.2259dupT | p.Gly754TrpfsTer28 | frameshift | Exon 15 of 18 | NP_000518.1 | ||
| LDLR | NM_001195798.2 | c.2259dupT | p.Gly754TrpfsTer28 | frameshift | Exon 15 of 18 | NP_001182727.1 | |||
| LDLR | NM_001195799.2 | c.2136dupT | p.Gly713TrpfsTer28 | frameshift | Exon 14 of 17 | NP_001182728.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| LDLR | ENST00000558518.6 | TSL:1 MANE Select | c.2259dupT | p.Gly754TrpfsTer28 | frameshift | Exon 15 of 18 | ENSP00000454071.1 | ||
| LDLR | ENST00000252444.10 | TSL:1 | c.2517dupT | p.Gly840TrpfsTer28 | frameshift | Exon 15 of 18 | ENSP00000252444.6 | ||
| LDLR | ENST00000558013.5 | TSL:1 | c.2259dupT | p.Gly754TrpfsTer28 | frameshift | Exon 15 of 18 | ENSP00000453346.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461800Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727200 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1461800
Hom.:
Cov.:
34
AF XY:
AC XY:
1
AN XY:
727200
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33480
American (AMR)
AF:
AC:
0
AN:
44704
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26136
East Asian (EAS)
AF:
AC:
0
AN:
39700
South Asian (SAS)
AF:
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
AC:
0
AN:
53400
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1111964
Other (OTH)
AF:
AC:
0
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
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2
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
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Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions as Germline
Significance:Pathogenic
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
1
-
-
Homozygous familial hypercholesterolemia (1)
1
-
-
Hypercholesterolemia, familial, 1 (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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