rs879255062

Positions:

• chr19-11120112-TATC-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_000527.5(LDLR):​c.1871_1873delTCA​(p.Ile624del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 2.21

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000527.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 19-11120112-TATC-T is Pathogenic according to our data. Variant chr19-11120112-TATC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 252097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120112-TATC-T is described in Lovd as [Pathogenic]. Variant chr19-11120112-TATC-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1871_1873delTCA	p.Ile624del	disruptive_inframe_deletion	13/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1871_1873delTCA	p.Ile624del	disruptive_inframe_deletion	13/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:7

Likely pathogenic, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 24, 2021	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

May 25, 2023

The LDLR c.1871_1873del (p.Ile624del) variant has been reported in the published literature in multiple individuals with familial hypercholesterolemia (PMIDs: 11668640 (2001), 15199436 (2004), 19318025 (2009), 20145306 (2010), 23375686 (2013), 28932795 (2015), 25378237 (2015), 27824480 (2017), and 31491741 (2019)). In vitro functional studies indicated that this variant results in significantly reduced LDLR expression, LDL binding, and LDL uptake compared to wild type (PMID: 25378237 (2015)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2022

The c.1871_1873delTCA pathogenic mutation (also known as p.I624del) is located in coding exon 13 of the LDLR gene. This pathogenic mutation results from an in-frame TCA deletion at nucleotide positions 1871 to 1873. This results in the in-frame deletion of an isoleucine at codon 624. This variant (also known as p.I603del) has been detected in several unrelated individuals with familial hypercholesterolemia (FH), FH cohorts, and cohorts referred for FH genetic testing (Leren TP et al. Atherosclerosis, 2021 04;322:61-66; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909; Tada H et al. J Clin Lipidol 2020 Mar;14:346-351.e9; Gabová D et al. Physiol Res, 2017 03;66:75-84; Etxebarria A et al. Hum Mutat, 2015 Jan;36:129-41; Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Chmara M et al. J Appl Genet, 2010;51:95-106). In a functional study, this variant was shown to result in significantly reduced LDLR expression, LDL binding, and LDL uptake compared to wild type (Etxebarria A et al. Hum Mutat, 2015 Jan;36:129-41). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2023

This variant, c.1871_1873del, results in the deletion of 1 amino acid(s) of the LDLR protein (p.Ile624del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with familial hypercholesterolemia (PMID: 11668640, 15199436, 20145306, 23375686, 25378237, 25461735, 27824480, 28932795). ClinVar contains an entry for this variant (Variation ID: 252097). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects LDLR function (PMID: 25378237). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs879255062; hg19: chr19-11230788;