rs747068848

Variant names:

• chr19-11089448-T-C
• rs747068848
• ENST00000913405.1:c.-101T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR): c.-101T>C variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, 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 Met: This variant is absent in gnomAD (gnomAD v2.1.1).PP4 Met: Variant meets PM2 and is identified in 1 index case who fulfil Simon Broome criteria for FH diagnosis (British Heart Foundation Laboratories, Centre for Cardiovascular Genetics, Institute of Cardiovascular Sciences, University College London,London, UK, PMID 22881376).PS3 not met: Heterologous cells (Huh7) were used in luciferase assay (level 3 functional assay), and have shown 64% reporter gene expression, which is greater than 50% compared to wild-type (Khamis et al 2015, Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute Cardiovascular Science, University College London Medicine School, London, UK, PMID 25248394). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584711/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: LDLR ENST00000913405.1 5_prime_UTR
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:5
• Conservation: PhyloP100: 0.132
• Publications: 4 publications found

Genes affected

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-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]

ENSG00000307752 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000913405.1. 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.212A>G		non_coding_transcript_exon	Exon 1 of 1
	LDLR	NM_000527.5	MANE Select	c.-101T>C		upstream_gene	N/A	NP_000518.1
	LDLR	NM_001195798.2		c.-101T>C		upstream_gene	N/A	NP_001182727.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000913405.1		c.-101T>C		5_prime_UTR	Exon 1 of 18	ENSP00000583464.1
	LDLR	ENST00000856646.1		c.-101T>C		5_prime_UTR	Exon 1 of 17	ENSP00000526705.1
	LDLR	ENST00000913412.1		c.-101T>C		5_prime_UTR	Exon 1 of 17	ENSP00000583471.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000524 AC: 4 AN: 762776 Hom.: 0 Cov.: 10 AF XY: 0.00000504 AC XY: 2 AN XY: 396840

African (AFR) AF: 0.00 AC: 0 AN: 19916

American (AMR) AF: 0.00 AC: 0 AN: 35300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19346

East Asian (EAS) AF: 0.00 AC: 0 AN: 35064

South Asian (SAS) AF: 0.00 AC: 0 AN: 66386

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2726

European-Non Finnish (NFE) AF: 0.00000793 AC: 4 AN: 504526

Other (OTH) AF: 0.00 AC: 0 AN: 36676

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	3	-	Hypercholesterolemia, familial, 1 (4)
-	1	-	Familial hypercholesterolemia (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.7
DANN	Benign	0.73
PhyloP100		0.13
PromoterAI		-0.66	Under-expression
Mutation Taster		=103/197	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: rs747068848; hg19: chr19-11200124; COSMIC: COSV52943610; COSMIC: COSV52943610;