rs730882090

chr19-11107420-C-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000527.5(LDLR):c.846C>A(p.Phe282Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,611,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F282C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:11 U:2 O:1
• Conservation: PhyloP100: 0.0430

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 16 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 9 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 19-11107420-C-A is Pathogenic according to our data. Variant chr19-11107420-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183098.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-11107420-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.846C>A	p.Phe282Leu	missense_variant	6/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.846C>A	p.Phe282Leu	missense_variant	6/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152132 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251430 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459566 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726126

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:11 Uncertain:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:8 Uncertain:1

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	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 20, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 15, 2023	This variant has been reported in multiple individuals with familial hypercholesterolemia (PMID: 34182004, 30592719, 22698793, 26666465, 29870584, 30270055, 35910211). Functional studies suggest that this variant results in a deleterious effect to the protein that is sufficient to be disease-causing (PMID: 25647241). This variant is present in 1/251430 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is predicted to be deleterious by in silico analysis. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	May 27, 2021	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Uncertain significance, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Apr 28, 2023	The NM_000527.5(LDLR):c.846C>A (p.Phe282Leu) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3_Supporting, PS4_Supporting, PM2, PP3, and 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: PS3_Supporting: Level 3 assays: PMID 25647241: HeLa cells, In vitro microscopy assays - result - 66% wild type LDLR expression (below 70%, Figure 3). ---- functional study is consistent with damaging effect. So, PS3_Supporting is met. PS4_Supporting: Variants meets PM2 and is identified in 2 cases from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille with diagnosis of probable FH based on DLCN criteria. So, PS4_Supporting is met. PM2: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes (gnomAD v2.1.1). So, PM2 is met. PP3: REVEL=0.877. It is above 0.75, so PP3 is met. PP4: Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details), after alternative causes for high cholesterol were excluded. -

not provided Pathogenic:2 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2022	Observed in individuals with familial hypercholesterolemia in published literature (Dukov et al., 2011; Do et al., 2015; Corral et al., 2018; Kose et al., 2020; Leren et al., 2021; Noto et al., 2022); Published functional studies demonstrate a damaging effect with reduced LDL-uptake (Thormaehlen et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25647241, 22698793, 21310417, 30270055, 26666465, 25487149, 32829317, 23833242, 33740630, 35339733) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	LDLR: PM2, PS3:Moderate, PS4:Moderate -
not provided, no classification provided	in vitro	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	-	- -

Familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 24, 2023

ClinVar contains an entry for this variant (Variation ID: 183098). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LDLR function (PMID: 25647241). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. This missense change has been observed in individuals with hypercholesterolemia (PMID: 21310417, 30270055, 30592719, 33740630, 35339733). This variant is present in population databases (rs730882090, gnomAD 0.0009%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 282 of the LDLR protein (p.Phe282Leu). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2020

The p.F282L variant (also known as c.846C>A), located in coding exon 6 of the LDLR gene, results from a C to A substitution at nucleotide position 846. The phenylalanine at codon 282 is replaced by leucine, an amino acid with highly similar properties, and is located in the ligand binding domain. This variant has been reported in hypercholesterolemia cohorts; however, clinical details were limited (Dušková L et al. Atherosclerosis, 2011 May;216:139-45; Tichý L et al. Atherosclerosis, 2012 Aug;223:401-8; Galaska R et al. J. Atheroscler. Thromb., 2016 May;23:588-95). This variant was also detected in an individual with history of myocardial infarction who had normal LDL-C levels, and limited functional studies suggested some impact on LDL uptake (Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855; Do R et al. Nature, 2015 Feb;518:102-6). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;.;.;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;.;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.0	D;D;D;D;D;D
Sift	Benign	0.033	D;D;D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D;D;D
Polyphen		0.40	B;.;.;.;.;.
Vest4		0.70
MutPred		0.83		Loss of methylation at K281 (P = 0.0527);Loss of methylation at K281 (P = 0.0527);.;.;.;Loss of methylation at K281 (P = 0.0527);
MVP		1.0
MPC		0.77
ClinPred		0.98	D
GERP RS		3.0
Varity_R		0.83
gMVP		0.90

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: rs730882090; hg19: chr19-11218096;