19-11089413-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NR_163945.1(LDLR-AS1):n.247G>A variant causes a non coding transcript exon change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LDLR-AS1
NR_163945.1 non_coding_transcript_exon

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 3.66

Publications

8 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-AS1 links:

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

LDLR links:

ENSG00000307752 (HGNC:):

ENSG00000307752 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-11089413-C-T is Pathogenic according to our data. Variant chr19-11089413-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 250955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.13). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NR_163945.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
LDLR-AS1	NR_163945.1		n.247G>A	non_coding_transcript_exon	Exon 1 of 1
LDLR	NM_000527.5	MANE Select	c.-136C>T	upstream_gene	N/A	NP_000518.1
LDLR	NM_001195798.2		c.-136C>T	upstream_gene	N/A	NP_001182727.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
LDLR	ENST00000558518.6	TSL:1 MANE Select	c.-136C>T	upstream_gene	N/A	ENSP00000454071.1
LDLR	ENST00000558013.5	TSL:1	c.-136C>T	upstream_gene	N/A	ENSP00000453346.1
LDLR	ENST00000557933.5	TSL:5	c.-136C>T	upstream_gene	N/A	ENSP00000453557.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

526298

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

275554

African (AFR)

AF:

0.00

AC:

AN:

14516

American (AMR)

AF:

0.00

AC:

AN:

23746

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15106

East Asian (EAS)

AF:

0.00

AC:

AN:

31404

South Asian (SAS)

AF:

0.00

AC:

AN:

51246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33640

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2132

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

325746

Other (OTH)

AF:

0.00

AC:

AN:

28762

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:3

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:literature only

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation;literature only

Nov 29, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Pathogenic:1

Mar 10, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.-136C>T pathogenic mutation is located in the 5' untranslated region (5’ UTR) of the LDLR gene. This variant results from a C to T substitution 136 nucleotides upstream from the first translated codon. This variant (also referred to as c.-43C>T) has been detected in several individuals with familial hypercholesterolemia (FH) and has been reported to segregate with hypercholesterolemia in families (Koivisto UM et al. Proc. Natl. Acad. Sci. U.S.A., 1994 Oct;91(22):10526-30; Jensen LG et al. Hum Mutat, 1996;7:82-4; Kim JH et al. Mol Cells, 2004 Aug;18(1):63-70; Fouchier SW et al. Hum Mutat, 2005 Dec;26:550-6; Leren TP et al. Atherosclerosis, 2021 04;322:61-66). Assays performed on cells from an individual with this mutation demonstrated reduced LDL receptor mRNA concentration and reduced LDL binding, internalization, and degradation compared to control cells (Jensen LG et al. Hum Mutat, 1996;7:82-4; Koivisto UM et al. Proc. Natl. Acad. Sci. U.S.A., 1994 Oct;91(22):10526-30). Functional studies indicate that this variant results in impaired promotor activity and reduced transcription levels compared to wild type (Koivisto UM et al. Proc. Natl. Acad. Sci. U.S.A., 1994 Oct;91(22):10526-30; Kircher M et al. Nat Commun, 2019 08;10:3583). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Familial hypercholesterolemia

Pathogenic:1

Jun 02, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant alters LDLR gene expression (PMID: 7937987). ClinVar contains an entry for this variant (Variation ID: 250955). This variant is also known as C-to-T substitution at position -43. This variant has been observed in individuals with familial hypercholesterolemia (PMID: 7937987, 8664911, 15199436, 15359125, 16250003). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This variant occurs in a non-coding region of the LDLR gene. It does not change the encoded amino acid sequence of the LDLR protein.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Uncertain

0.98

PhyloP100

3.7

PromoterAI

-0.93

Under-expression

(source)

Mutation Taster

=100/200

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over