rs879254367

Variant names:

• chr19-11089397-C-T
• rs879254367
• NR_163945.1:n.263G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PS3 PM2 PP5_Very_Strong BP4

The NR_163945.1(LDLR-AS1):​n.263G>A variant causes a non coding transcript exon change. The variant allele was found at a frequency of 0.0000086 in 465,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004836275: "In vitro functional studies have shown that this variant causes a 30-40% reduction in LDLR promoter activity." PMID:10484771, 31395865" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: LDLR-AS1 NR_163945.1 non_coding_transcript_exon
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 U:1
• Conservation: PhyloP100: 3.66
• Publications: 5 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: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004836275: "In vitro functional studies have shown that this variant causes a 30-40% reduction in LDLR promoter activity." PMID: 10484771, 31395865; SCV000752416: Studies have shown that this variant alters LDLR gene expression (PMID: 10484771).; SCV001434981: Functional studies have shown reduced promoter activity of the LDLR gene when this variant is present (PMID: 10484771).; SCV006061100: "In vitro functional studies have shown that this variant causes a 30-40% reduction in LDLR promoter activity." PMID: 10484771, 31395865; SCV002706639: Functional studies showed reduction in promoter activity and transcription (Scholtz CL et al. Hum Mol Genet, 1999 Oct;8:2025-30; Kircher M et al. Nat Commun, 2019 08;10:3583).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-11089397-C-T is Pathogenic according to our data. Variant chr19-11089397-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 250945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.1). . 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR-AS1	NR_163945.1		n.263G>A		non_coding_transcript_exon	Exon 1 of 1
	LDLR	NM_000527.5	MANE Select	c.-152C>T		upstream_gene	N/A	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.-152C>T		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.-152C>T		upstream_gene	N/A	ENSP00000454071.1	P01130-1
	LDLR	ENST00000558013.5	TSL:1	c.-152C>T		upstream_gene	N/A	ENSP00000453346.1	P01130-5
	LDLR	ENST00000557933.5	TSL:5	c.-152C>T		upstream_gene	N/A	ENSP00000453557.1	H0YMD1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000860 AC: 4 AN: 465096 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 243796

African (AFR) AF: 0.00 AC: 0 AN: 12816

American (AMR) AF: 0.00 AC: 0 AN: 19860

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14020

East Asian (EAS) AF: 0.00 AC: 0 AN: 30542

South Asian (SAS) AF: 0.00 AC: 0 AN: 46626

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1968

European-Non Finnish (NFE) AF: 0.0000106 AC: 3 AN: 281748

Other (OTH) AF: 0.0000378 AC: 1 AN: 26458

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000296 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	1	-	Hypercholesterolemia, familial, 1 (5)
3	-	-	Familial hypercholesterolemia (3)
1	-	-	Cardiovascular phenotype (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Benign	0.96
PhyloP100		3.7
PromoterAI		-0.024	Neutral
Mutation Taster		=268/32	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: rs879254367; hg19: chr19-11200073;