rs879254364

Variant names:

• chr19-11089393-C-T
• rs879254364
• NR_163945.1:n.267G>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM2 PP5_Strong BP4

The NR_163945.1(LDLR-AS1):​n.267G>A variant causes a non coding transcript exon change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LDLR-AS1 NR_163945.1 non_coding_transcript_exon
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:3
• Conservation: PhyloP100: 3.66

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-11089393-C-T is Pathogenic according to our data. Variant chr19-11089393-C-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 250942.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=3, Pathogenic=1}. Variant chr19-11089393-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.11). . 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.-156C>T		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.-156C>T		upstream_gene_variant		1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 455202 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 238662

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1 Uncertain:2

Nov 20, 2023

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 SREBP binding site in the promoter region of the LDLR gene. An experimental functional study measuring luciferase activity in transfected HepG2 cells has shown that this variant causes a significant decrease in LDLR gene expression (PMID: 31395865). This variant has been reported in four heterozygous individuals affected with familial hypercholesterolemia (PMID: 14974088, 21382890, 28104544, 33740630). This variant has also been observed in homozygous state in one individual affected with severe homozygous familial hypercholesterolemia (PMID: 31947532, 32977124). It has been shown that this variant segregates with disease in two affected individuals in one family (PMID: 14974088). 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

- -

Mar 20, 2023

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.4(LDLR):c.-156C>T variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PS3_supporting, PS4_supporting, PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PS3_supporting - Level 3 assay: PMID 31395865: Heterologous cells, luciferase assays - result - luciferase activity 15-17% of wild-type (repressing variant). ---- functional study is consistent with damaging effect. PS4_supporting - Variant meets PM2 and is identified in 2 index cases with definite FH: 1 index case with CT=439, LDL=377, severe CAD and Achilles tendon xanthomata from Germany (PMID: 14974088), and 1 index case with LDL >13 mmol/L, pCHD and tendon xanthomas from Italy (PMID: 31947532). PP4 - Variant meets PM2 and is identified in 2 index cases with definite FH (see PS4 for details), after alternative causes for high cholesterol were excluded. -

Cardiovascular phenotype Pathogenic:1

May 24, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-156C>T variant is located in the 5' untranslated region (5’ UTR) of the LDLR gene. This variant results from a C to T substitution 156 nucleotides upstream from the first translated codon, and is located in the sterol regulatory element (SRE-1). This variant was reported to occur in the homozygous state in an individual with features consistent with homozygous familial hypercholesterolemia (FH) including severe, early onset coronary artery disease, LDL-C of 377mg/dL, Achilles tendon xanthoma, periorbital xanthelasma, and sudden death who also had a family history of heart attack, sudden death, and hypercholesterolemia; a reportedly less severely affected sibling was heterozygous for the variant (Dedoussis GV et al. Hum. Mutat., 2004 Mar;23:285-6). This has also been detected in the heterozygous state in individuals with features consistent with heterozygous FH or individuals from FH cohorts; however, in some cases clinical details were limited (van der Graaf A et al. Circulation. 2011 Mar;123(11):1167-73; Durst R et al. Atherosclerosis, 2017 02;257:55-63; Leren TP et al. Atherosclerosis. 2021 Apr;322:61-66). This nucleotide position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial hypercholesterolemia Pathogenic:1

Nov 11, 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 hypercholesterolemia (PMID: 14974088, 21382890, 28104544, 32977124, 33740630). 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: 250942). Studies have shown that this variant alters LDLR gene expression (PMID: 31395865). For these reasons, this variant has been classified as Pathogenic. -

not provided Uncertain:1

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LDLR: PM1, PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Benign	0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs879254364; hg19: chr19-11200069; COSMIC: COSV99370387; COSMIC: COSV99370387;