rs387906307

Variant names:

• chr19-11089410-CT-C
• rs387906307
• NR_163945.1:n.249delA

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS3 PM2 PP5

The NR_163945.1(LDLR-AS1):​n.249delA variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV004840284: Functional studies using lymphocytes derived from a heterozygous individual have shown that this variant resulted in reduced LDLR activity and absent mRNA transcription (PMID:14616764). An in-vitro functional study using transfected mammalian cells has shown that this variant causes a significant reduction in promoter activity (PMID:14616764, 17625505)." and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR-AS1 NR_163945.1 non_coding_transcript_exon
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:2
• Conservation: PhyloP100: 0.859
• Publications: 6 publications found

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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000307752 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004840284: Functional studies using lymphocytes derived from a heterozygous individual have shown that this variant resulted in reduced LDLR activity and absent mRNA transcription (PMID: 14616764). An in-vitro functional study using transfected mammalian cells has shown that this variant causes a significant reduction in promoter activity (PMID: 14616764, 17625505).; SCV006063578: Functional studies using lymphocytes derived from a heterozygous individual have shown that this variant resulted in reduced LDLR activity and absent mRNA transcription (PMID: 14616764). An in-vitro functional study using transfected mammalian cells has shown that this variant causes a significant reduction in promoter activity (PMID: 14616764, 17625505).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-11089410-CT-C is Pathogenic according to our data. Variant chr19-11089410-CT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3745.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR-AS1	NR_163945.1		n.249delA		non_coding_transcript_exon	Exon 1 of 1
	LDLR	NM_000527.5	MANE Select	c.-138delT		upstream_gene	N/A	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.-138delT		upstream_gene	N/A	NP_001182727.1	P01130-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.-138delT		upstream_gene	N/A	ENSP00000454071.1	P01130-1
	LDLR	ENST00000558013.5	TSL:1	c.-138delT		upstream_gene	N/A	ENSP00000453346.1	P01130-5
	LDLR	ENST00000557933.5	TSL:5	c.-138delT		upstream_gene	N/A	ENSP00000453557.1	H0YMD1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 7

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	-	-	Hypercholesterolemia, familial, 1 (4)
1	1	-	Familial hypercholesterolemia (2)
-	1	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.86
Mutation Taster		=282/18	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

Other links and lift over

dbSNP: rs387906307; hg19: chr19-11200086;