dbSNP rs879254359: LDLR-AS1:n.335dupT (chr19-11089324-T-TA) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NR_163945.1(LDLR-AS1):n.335dupT variant causes a non coding transcript exon change. The variant allele was found at a frequency of 0.00000285 in 350,664 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: 0.0000029 ( 0 hom. )

Consequence

LDLR-AS1
NR_163945.1 non_coding_transcript_exon

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.17

Publications

0 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:

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
LDLR	NM_000527.5 link	c.-225_-224insA		upstream_gene_variant		ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.-225_-224insA		upstream_gene_variant		1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000285

AC:

AN:

350664

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

183174

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

9508

American (AMR)

AF:

0.00

AC:

AN:

12018

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11402

East Asian (EAS)

AF:

0.00

AC:

AN:

25514

South Asian (SAS)

AF:

0.00

AC:

AN:

27790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26644

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1606

European-Non Finnish (NFE)

AF:

0.00000465

AC:

AN:

214952

Other (OTH)

AF:

0.00

AC:

AN:

21230

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Uncertain:1

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:literature only

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.2

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over