chr19-11089429-C-T

Variant names:

• chr19-11089429-C-T
• rs875989886
• ENST00000913405.1:c.-120C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PS3_Supporting PM2 PP4 PP1 PS4_Supporting BP2

This summary comes from the ClinGen Evidence Repository: The NM_000527.4(LDLR):c.-120C>T variant is classified as Uncertain significance - conflicting evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP1, PP4, PS3_Supporting, PS4_Supporting and BP2 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 - PopMax MAF = 0.00001470 (0.001470%) in European non-Finnish (gnomAD v3.2.1). It is below 0.02%, so met.PP1 - Variant segregates with the FH phenotype in:- 2 relatives from 1 family from Francová et al. 2004 (PMID:15303010): 2 relatives with the phenotype (LDL cholesterol concentration between 93 and 99.5 percentile for age and sex) have the variant;- 1 relative from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA): 1 relative without the phenotype and without the variant.3 segregations, so PP1 is met.PS3_supporting - Level 3 FS: Francová et al. 2004 (PMID:15303010) : Heterologous cells (HepG2), luciferase assays - results: 3% reporter gene transcription (Reported as c.-27C>T in the paper).--- it is below 50%, so PS3_Supporting is met.PS4_supporting - variant meets PM2 and was identified in:- 1 index case with Simon Broome possible from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France;- 1 index case with Simon Broome possible from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czech Republic;- 1 index case with Dutch lipid clinic network >=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), Australia.3 cases, so PS4_Supporting is metPP4 - variant meets PM2 and was identified in 3 unrelated index cases who fulfill clinical FH criteria from different labs (please see PS4 for details), so PP4 is met.BP2 - Variant identified in 1 index case and 1 relative, both carriers of NM_000527.4(LDLR):c.2416dupG (p.Val806Glyfs*11) in trans with LDLc values of 4.3 mmol/l (16y) and 5.9 mmol/l (11y), respectively. 2nd variant is classified as Pathogenic by these guidelines and phenotype is clearly of heterozygous FH, so BP2 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10576265/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: LDLR ENST00000913405.1 5_prime_UTR
• Clinical Significance: Uncertain significance reviewed by expert panel P:5 U:6 B:1
• Conservation: PhyloP100: 2.11
• 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

Specifications for LDLR are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP2: 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.231G>A		non_coding_transcript_exon	Exon 1 of 1
	LDLR	NM_000527.5	MANE Select	c.-120C>T		upstream_gene	N/A	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.-120C>T		upstream_gene	N/A	NP_001182727.1	P01130-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000913405.1		c.-120C>T		5_prime_UTR	Exon 1 of 18	ENSP00000583464.1
	LDLR	ENST00000913412.1		c.-120C>T		5_prime_UTR	Exon 1 of 17	ENSP00000583471.1
	LDLR	ENST00000913406.1		c.-120C>T		5_prime_UTR	Exon 1 of 16	ENSP00000583465.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152192 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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000311 AC: 19 AN: 610234 Hom.: 0 Cov.: 8 AF XY: 0.0000281 AC XY: 9 AN XY: 319782

African (AFR) AF: 0.00 AC: 0 AN: 16584

American (AMR) AF: 0.00 AC: 0 AN: 28328

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16734

East Asian (EAS) AF: 0.00 AC: 0 AN: 32924

South Asian (SAS) AF: 0.0000175 AC: 1 AN: 57294

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2336

European-Non Finnish (NFE) AF: 0.0000336 AC: 13 AN: 386816

Other (OTH) AF: 0.000158 AC: 5 AN: 31630

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74478

African (AFR) AF: 0.00 AC: 0 AN: 41580

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000269 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	2	1	Hypercholesterolemia, familial, 1 (7)
1	2	-	Familial hypercholesterolemia (3)
-	1	-	Cardiovascular phenotype (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.56
PhyloP100		2.1
PromoterAI		-0.19	Neutral
Mutation Taster		=95/205	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: rs875989886; hg19: chr19-11200105;