NR_163945.1:n.246G>C

Variant names:

• chr19-11089414-C-G
• rs879254375
• NR_163945.1:n.246G>C

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.246G>C 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 0.00000293 in 682,148 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: "SCV000915811: Functional studies demonstrated that the variant resulted in between 5-15% of LDL receptor activity (Hobbs et al. 1992" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: LDLR-AS1 NR_163945.1 non_coding_transcript_exon
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: 2.27
• 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: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000915811: Functional studies demonstrated that the variant resulted in between 5-15% of LDL receptor activity (Hobbs et al. 1992; De Castro-Oros et al. 2011).; SCV004839110: Functional studies have shown that this variant causes a significant decrease in LDLR promoter activity (PMID: 21538688), and that the mutant protein shows a significant reduction in LDLR activity (PMID: 1301956).; SCV000544670: Studies have shown that this variant alters LDLR gene expression (PMID: 19411563, 21538688).; SCV001734616: Functional studies have shown that this variant causes a significant decrease in LDLR promoter activity (PMID: 21538688), and that the mutant protein shows a significant reduction in LDLR activity (PMID: 1301956).; SCV002697540: Functional studies demonstrated significantly reduced LDLR activity in cells with this variant (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; De Castro-Orós I et al. Hum. Mutat., 2011 Aug;32:868-72).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-11089414-C-G is Pathogenic according to our data. Variant chr19-11089414-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 250956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29). . 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.246G>C		non_coding_transcript_exon	Exon 1 of 1
	LDLR	NM_000527.5	MANE Select	c.-135C>G		upstream_gene	N/A	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.-135C>G		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.-135C>G		upstream_gene	N/A	ENSP00000454071.1	P01130-1
	LDLR	ENST00000558013.5	TSL:1	c.-135C>G		upstream_gene	N/A	ENSP00000453346.1	P01130-5
	LDLR	ENST00000557933.5	TSL:5	c.-135C>G		upstream_gene	N/A	ENSP00000453557.1	H0YMD1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00000189 AC: 1 AN: 529948 Hom.: 0 Cov.: 7 AF XY: 0.00000360 AC XY: 1 AN XY: 277594

African (AFR) AF: 0.00 AC: 0 AN: 14568

American (AMR) AF: 0.00 AC: 0 AN: 23892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15178

East Asian (EAS) AF: 0.00 AC: 0 AN: 31410

South Asian (SAS) AF: 0.00 AC: 0 AN: 51506

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33790

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2142

European-Non Finnish (NFE) AF: 0.00000304 AC: 1 AN: 328562

Other (OTH) AF: 0.00 AC: 0 AN: 28900

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
11	-	-	Hypercholesterolemia, familial, 1 (11)
3	-	-	Familial hypercholesterolemia (3)
2	-	-	not provided (2)
1	-	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Benign	0.84
PhyloP100		2.3
PromoterAI		-0.87	Under-expression
Mutation Taster		=90/210	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: rs879254375; hg19: chr19-11200090;