19-11089410-C-G

Variant names:

• chr19-11089410-C-G
• rs879254371
• NR_163945.1:n.250G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NR_163945.1(LDLR-AS1):​n.250G>C variant causes a non coding transcript exon change. The variant allele was found at a frequency of 0.00000597 in 669,682 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: LDLR-AS1 NR_163945.1 non_coding_transcript_exon
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 3.66
• Publications: 8 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000307752 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-11089410-C-G is Pathogenic according to our data. Variant chr19-11089410-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 250951.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.13). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.-139C>G		upstream_gene_variant		ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.-139C>G		upstream_gene_variant		1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.00

GnomAD4 exome AF: 0.00000193 AC: 1 AN: 517480 Hom.: 0 Cov.: 7 AF XY: 0.00 AC XY: 0 AN XY: 270964

African (AFR) AF: 0.0000699 AC: 1 AN: 14302

American (AMR) AF: 0.00 AC: 0 AN: 23360

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14970

East Asian (EAS) AF: 0.00 AC: 0 AN: 31280

South Asian (SAS) AF: 0.00 AC: 0 AN: 50626

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2126

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 319264

Other (OTH) AF: 0.00 AC: 0 AN: 28440

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74352

African (AFR) AF: 0.0000724 AC: 3 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15274

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: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2 Uncertain:1

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

Mar 24, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is located in the 5' untranslated region of the LDLR gene. Functional studies using a luciferase assay in transfected Huh7 cells have shown that this variant causes a >70% reduction in promoter activity, as well as abrogated Sp1 binding (PMID: 17625505). This variant has been reported in at least three individuals affected with familial hypercholesterolemia (PMID: 17625505, 20236128; ClinVar SCV003442707.2). It has been shown that this variant segregates with disease in two affected individuals from one family (PMID: 17625505). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

Cardiovascular phenotype Pathogenic:1

Jun 25, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-139C>G variant is located in the 5' untranslated region (5’ UTR) of the LDLR gene. This variant results from a C to G substitution 139 bases upstream from the first translated codon. This variant was identified in one or more individuals with features consistent with familial hypercholesterolemia (FH) and segregated with disease in at least one family (Smith AJ et al. Eur J Hum Genet, 2007 Nov;15:1186-9; Taylor A et al. Clin Genet, 2010 Jun;77:572-80; external communication; Ambry internal data). In an assay testing LDLR function, this variant showed a functionally abnormal result (Smith AJ et al. Eur J Hum Genet, 2007 Nov;15:1186-9). 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 majority of available evidence to date, this variant is likely to be pathogenic.

Familial hypercholesterolemia Pathogenic:1

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 17625505; internal data). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. ClinVar contains an entry for this variant (Variation ID: 250951). Studies have shown that this variant alters LDLR gene expression (PMID: 17625505). For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Benign	0.94
PhyloP100		3.7
PromoterAI		-0.93	Under-expression
Mutation Taster		=15/285	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: rs879254371; hg19: chr19-11200086;