19-11089409-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NR_163945.1(LDLR-AS1):​n.251G>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000194 in 514,340 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000019 ( 0 hom. )

Consequence

LDLR-AS1
NR_163945.1 non_coding_transcript_exon

Scores

2

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:3

Conservation

PhyloP100: 2.19

Publications

6 publications found
Variant links:
Genes affected
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]
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, 1
    Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
  • homozygous familial hypercholesterolemia
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LDLRNM_000527.5 linkc.-140C>A upstream_gene_variant ENST00000558518.6 NP_000518.1 P01130-1A0A024R7D5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LDLRENST00000558518.6 linkc.-140C>A upstream_gene_variant 1 NM_000527.5 ENSP00000454071.1 P01130-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000194
AC:
1
AN:
514340
Hom.:
0
Cov.:
7
AF XY:
0.00000371
AC XY:
1
AN XY:
269310
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
14240
American (AMR)
AF:
0.00
AC:
0
AN:
23308
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
14944
East Asian (EAS)
AF:
0.00
AC:
0
AN:
31224
South Asian (SAS)
AF:
0.0000198
AC:
1
AN:
50466
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
33004
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
2106
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
316782
Other (OTH)
AF:
0.00
AC:
0
AN:
28266
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
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
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:3
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1Uncertain:3
Aug 29, 2022
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel
Significance:Uncertain significance
Review Status:reviewed by expert panel
Collection Method:curation

The NM_000527.5(LDLR): NM_000527.4(LDLR):c.-140C>A variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PP4 - Variant meets PM2 and is identified in one index case who fulfill SB criteria for FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) after alternative causes of high cholesterol were excluded. -

Mar 01, 2016
Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:research

- -

Nov 05, 2016
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Disrupt SP1 site sequence. -

Mar 01, 2016
Iberoamerican FH Network
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Uncertain
-0.030
CADD
Benign
22
DANN
Uncertain
0.99
PhyloP100
2.2
PromoterAI
-0.83
Under-expression
Mutation Taster
=27/273
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs875989887; hg19: chr19-11200085; API