rs140241383

Positions:

• chr19-11107432-C-A
• chr19-11107432-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3 PP1 PP4 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.858C>A (p.Ser286Arg) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_Supporting, PP1, 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:PM2 - PopMax MAF = 0.00006155 (0.006155%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1).PS4_Supporting - Variant meets PM2 and is identified in 4 unrelated index cases who fulfil DLCN >=6 (1 case in PMID:32770674; 2 cases from Robarts Research Institute) or SB definitive ( 1 case from Molecular Genetics Laboratory of Centre for Cardiovascular Surgery and Transplantation).PP1 - Variant segregates with FH phenotype in 2 informative meiosis from 2 unrelated families (1 case from Molecular Genetics Laboratory of Centre for Cardiovascular Surgery and Transplantation and 1 case from Robarts Research Institute).PP3 - REVEL = 0.766.PP4 - Variant meets PM2 and is identified in 4 index cases who fulfil DLCN >=6 (1 case in PMID:32770674; 2 cases from Robarts Research Institute) or SB definitive ( 1 case from Molecular Genetics Laboratory of Centre for Cardiovascular Surgery and Transplantation). LINK:https://erepo.genome.network/evrepo/ui/classification/CA029904/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:25 U:1
• Conservation: PhyloP100: -1.35

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 Likely_pathogenic. Variant got 6 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.858C>A	p.Ser286Arg	missense_variant	6/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.858C>A	p.Ser286Arg	missense_variant	6/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000278 AC: 7 AN: 251430 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135904

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: 0.0000616

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1459096 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 725868

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: 0.0000162

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000294 Hom.: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:25 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:13 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 28, 2021	The p.Ser286Arg variant in LDLR has been reported in more than 25 individuals with hypercholesterolemia and segregated with disease in at least 27 affected individuals from multiple families (Hobbs 1992 PMID: 1301956, Bertolini 2013 PMID: 23375686, Mollaki 2014 PMID: 27578104). Notably, the variant appears to be associated with a milder hypercholesterolemia phenotype (Huijgen 2012 PMID: 22390909). This variant has also been reported in by other clinical laboratories in ClinVar (Variation ID 251488) and has been identified in 0.006% (7/113726) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of familial hypercholesterolemia (FH) in the general population. In vitro functional studies support an impact on protein function (Hobbs 1992 PMID: 1301956) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2_supporting, PS3_Supporting, PP3. -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	May 23, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	May 05, 2022	PM1, PM2, PP2, PP3, PP5 -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 14, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 16, 2022	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jan 19, 2022	NM_000527.5(LDLR):c.858C>A (p.Ser286Arg) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_Supporting, PP1, 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: PM2 - PopMax MAF = 0.00006155 (0.006155%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1). PS4_Supporting - Variant meets PM2 and is identified in 4 unrelated index cases who fulfil DLCN >=6 (1 case in PMID: 32770674; 2 cases from Robarts Research Institute) or SB definitive ( 1 case from Molecular Genetics Laboratory of Centre for Cardiovascular Surgery and Transplantation). PP1 - Variant segregates with FH phenotype in 2 informative meiosis from 2 unrelated families (1 case from Molecular Genetics Laboratory of Centre for Cardiovascular Surgery and Transplantation and 1 case from Robarts Research Institute). PP3 - REVEL = 0.766. PP4 - Variant meets PM2 and is identified in 4 index cases who fulfil DLCN >=6 (1 case in PMID: 32770674; 2 cases from Robarts Research Institute) or SB definitive ( 1 case from Molecular Genetics Laboratory of Centre for Cardiovascular Surgery and Transplantation). -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
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	subjects mutated among 2600 FH index cases screened = 6 / FH-Greece-2, 5 to 15% LDLR Activity / Software predictions: Conflicting -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 14, 2023	This missense variant (also known as p.Ser265Arg in the mature protein and as FH Greece-2) replaces serine with arginine at codon 286 in the LDLR type A repeat 7 of the ligand binding domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental functional study has shown that this variant in compound heterozygosity with p.Cys173Arg reduces LDLR activity to 5-15% compared to wild type (PMID: 1301956). This variant has been reported in numerous individuals affected with familial hypercholesterolemia (PMID: 11462246, 11810272, 15015036, 17347910, 23130880, 27578104, 27765764, 28965616, 32829317, 33454241, 33794673; Color Health internal data) and is a recurrent mutation in the Greek population (PMID: 27578104). This variant has been identified in 7/251430 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

not provided Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 24, 2019	The best available variant frequency is uninformative. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 01, 2022	PP3, PM2_supporting, PS3_moderate, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	LDLR: PM1, PM2, PP4:Moderate, PS4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2022	Published functional studies demonstrate a damaging effect, including a reduction in LDLR activity (Hobbs et al., 1992); 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: 14974088, 22390909, 15015036, 11462246, 23375686, 27578104, 25463123, 28965616, 34426522, 33303402, 32719484, 32770674, 32977124, 34037665, 1301956) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Jul 25, 2022	PS4, PP3, PM2_SUP -

Familial hypercholesterolemia Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 29, 2023	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 286 of the LDLR protein (p.Ser286Arg). This variant is present in population databases (rs140241383, gnomAD 0.007%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 11317361, 11462246, 15015036, 23130880, 27765764). This variant is also known as p.Ser265Arg. ClinVar contains an entry for this variant (Variation ID: 251488). 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. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 06, 2017	Variant summary: The LDLR c.858C>A (p.Ser286Arg) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index), which was confirmed by low LDLR activity in patient carrying this variant (Hobbs_1992). This variant was found in 3/121368 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). This variant has been reported in a large number of FH patients with milder phenotype. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 02, 2023	This missense variant replaces serine with arginine at codon 286 in the LDLR type A repeat 7 of the ligand binding domain of the LDLR protein. This variant is also known as p.Ser265Arg in the mature protein and as FH Greece-2 in the literature. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental functional study has shown that this variant in compound heterozygosity with p.Cys173Arg reduces LDLR activity to 5-15% compared to wild type (PMID: 1301956). This variant has been reported in over 150 individuals affected with familial hypercholesterolemia (PMID: 11462246, 11810272, 15015036, 17347910, 23130880, 27578104, 27765764, 28965616, 32829317, 33454241, 33794673; Color Health internal data) and is a recurrent mutation in the Greek population (PMID: 27578104). This variant has been identified in 7/251430 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2023

The p.S286R pathogenic mutation (also known as c.858C>A), located in coding exon 6 of the LDLR gene, results from a C to A substitution at nucleotide position 858. The serine at codon 286 is replaced by arginine, an amino acid with dissimilar properties, and is located in the ligand binding 7 domain. This alteration, also referred to as S265R and FH Greece-2, has been detected in several cohorts and multiple unrelated individuals with hypercholesterolemia from various ethnic backgrounds, and has been reported to result in reduced LDL receptor activity (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Day IN et al. Hum. Mutat., 1997;10:116-27; Traeger-Synodinos J et al. Hum. Genet., 1998 Mar;102:343-7; Nauck MS et al. Hum. Mutat., 2001 Aug;18:165-6; Mihaylov VA et al. J. Hum. Genet., 2004 Mar;49:173-6; Whittall RA et al. Ann. Clin. Biochem., 2010 Jan;47:44-55; Huijgen R et al. Eur. Heart J., 2012 Sep;33:2325-30; Mollaki V et al. Atherosclerosis, 2014 Dec;237:798-804; Klanar G et al. J. Am. Coll. Cardiol., 2015 Sep;66:1250-1257). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.43
CADD	Benign	6.7
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D;.;.;.;.;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.41	N
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M;.;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.9	D;D;D;D;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0030	D;D;D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D;D;D
Polyphen		0.99	D;.;.;.;.;.
Vest4		0.67
MutPred		0.66		Gain of ubiquitination at K283 (P = 0.0798);Gain of ubiquitination at K283 (P = 0.0798);.;.;.;Gain of ubiquitination at K283 (P = 0.0798);
MVP		1.0
MPC		0.85
ClinPred		0.80	D
GERP RS		-6.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.91

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: rs140241383; hg19: chr19-11218108;