rs137943601

Positions:

• chr19-11113313-G-A
• chr19-11113313-G-C
• chr19-11113313-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP3 PP1 PP4 PS3_Moderate PS4_Moderate

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.1222G>A (p.Glu408Lys) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS3_Moderate, PS4_Moderate, PP1, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00001763 (0.0018%) in European non-Finnish exomes (gnomAD v2.1.1). PS3_moderate - Level 2 assay: PMID:1301956 - study on hmz patient's fibroblasts, 125I-LDL assay, effect value reported as <2%; Level 2 assay: PMID:9026534 - Epstein-Barr virus-transformed lymphoblasts from hmz patient, 125I-LDL assays - Results - 5-10% LDLR activity.PS4_moderate - Variant meets PM2. Variant identified in 8 index cases (1 case from Center of molecular biology and gene therapy with Simon-Broome criteria; 1 case from GeneDx laboratory with Simon Broome criteria, 1 case from Color laboratory with Simon Broome criteria, 1 case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with Simon Broome criteria, 1 case from University of British Columbia with DLCN criteria, 1 case from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge with Simon-Broome criteria, 2 cases from Ambry Genetics with Simon-Broome criteria).PP1 - Variant segregates with phenotype in 2 members of family (2 meiosis) from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.PP3 - REVEL: 0,879. Score is above 0,75.PP4 - Variant meets PM2. Variant identified in 8 index cases (see PS4_Moderate). LINK:https://erepo.genome.network/evrepo/ui/classification/CA023437/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:21 B:1
• Conservation: PhyloP100: 9.82

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 9 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.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1222G>A	p.Glu408Lys	missense_variant	9/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1222G>A	p.Glu408Lys	missense_variant	9/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251104 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135846

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461428 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727028

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

Alfa AF: 0.000142 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:21 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:13

Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 09, 2021	NM_000527.5(LDLR):c.1222G>A (p.Glu408Lys) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS3_Moderate, PS4_Moderate, PP1, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00001763 (0.0018%) in European non-Finnish exomes (gnomAD v2.1.1). PS3_moderate - Level 2 assay: PMID:1301956 - study on hmz patient's fibroblasts, 125I-LDL assay, effect value reported as <2%; Level 2 assay: PMID: 9026534 - Epstein-Barr virus-transformed lymphoblasts from hmz patient, 125I-LDL assays - Results - 5-10% LDLR activity. PS4_moderate - Variant meets PM2. Variant identified in 8 index cases (1 case from Center of molecular biology and gene therapy with Simon-Broome criteria; 1 case from GeneDx laboratory with Simon Broome criteria, 1 case from Color laboratory with Simon Broome criteria, 1 case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with Simon Broome criteria, 1 case from University of British Columbia with DLCN criteria, 1 case from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge with Simon-Broome criteria, 2 cases from Ambry Genetics with Simon-Broome criteria). PP1 - Variant segregates with phenotype in 2 members of family (2 meiosis) from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. PP3 - REVEL: 0,879. Score is above 0,75. PP4 - Variant meets PM2. Variant identified in 8 index cases (see PS4_Moderate). -
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 = 10 , family members = 5 with co-segregation / FH-Algérie-1/Osaka, <2% LDLR Activity / Software predictions: Conflicting -
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	- -
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	Fulgent Genetics, Fulgent Genetics	Aug 12, 2021	- -
Likely pathogenic, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/208 non-FH alleles -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 23, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Apr 28, 2023	This missense variant (also known as p.Glu387Lys in the mature protein and as FH-Algeria-1) replaces glutamic acid with lysine at codon 408 in the EGF precursor homology 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). Functional studies have shown that this variant causes a significant decrease in LDLR function due to impaired LDLR recycling and increased protein degradation in lysosomes (PMID: 9026534, 1301956, 19026292, 2153120). This variant has been reported in many unrelated individuals affected with familial hypercholesterolemia (PMID: 1301956, 9026534, 9698020, 12436241, 14974088, 15199436, 16250003, 17094996, 17347910, 17765246, 18022922, 19843101, 22698793, 29353225, 29396260, 30415195). This variant has also been reported in two unrelated individuals affected with homozygous familial hypercholesterolemia (PMID: 9026534, 19026292). This variant has been identified in 2/251104 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Aug 25, 2011	- -
Likely pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Nov 29, 2018	- -

Familial hypercholesterolemia Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 16, 2019	Variant summary: LDLR c.1222G>A (p.Glu408Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251304 control chromosomes (gnomAD). The variant, c.1222G>A, has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Hobbs_1992, Webb_1996). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Hobbs_1992, Webb_1996). Eight ClinVar submissions (evaluation after 2014) cite the variant twice as pathogenic and six times as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 408 of the LDLR protein (p.Glu408Lys). This variant is present in population databases (rs137943601, gnomAD 0.002%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 1301956, 14974088, 17347910, 19843101, 20236128). This variant is also known as FH Algeria-1 or E387K. ClinVar contains an entry for this variant (Variation ID: 36453). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LDLR function (PMID: 1301956, 21531209). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 08, 2023	This missense variant (also known as p.Glu387Lys in the mature protein and as FH-Algeria-1) replaces glutamic acid with lysine at codon 408 in the EGF precursor homology 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). Functional studies have shown that this variant causes a significant decrease in LDLR function due to impaired LDLR recycling and increased protein degradation in lysosomes (PMID: 9026534, 1301956, 19026292, 2153120). This variant has been reported in many unrelated individuals affected with familial hypercholesterolemia (PMID: 1301956, 9026534, 9698020, 12436241, 14974088, 15199436, 16250003, 17094996, 17347910, 17765246, 18022922, 19843101, 22698793, 29353225, 29396260, 30415195). This variant has also been reported in two unrelated individuals affected with homozygous familial hypercholesterolemia (PMID: 9026534, 19026292). This variant has been identified in 2/251104 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jun 17, 2019	This c.1222G>A (p.Glu408Lys) variant in the LDLR gene has been reported in multiple unrelated individuals affected with familial hypercholesteromeia (PMID 1301956, 9026534, 16250003, 17347910, 21531209) and myocardial infarction (PMID 25487149). LDL-R activity in cells derived from affected individuals was under 10% compared to wildtype (PMID 1301956, 9026534). This variant is extremely rare in general population databases. Multiple lines of algorithms predicted this p.Glu408Lys change to be deleterious. Therefore, this c.1222G>A (p.Glu408Lys) variant in the LDLR gene is classified pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 16, 2023	The frequency of this variant in the general population, 0.000008 (2/251104 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in several individuals with Familial Hypercholesterolemia (FH) (PMID: 1301956 (1992), 9026534 (1996), 12436241 (2002), 14974088 (2004), 15199436 (2004), 17347910 (2007)), and has been found to segregate with disease in family members (PMID: 32163632 (2020)). Functional studies have reported this variant has a damaging effect on LDLR activity (PMID: 1301956 (1992)), 9026534 (1996)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2024	Observed in the heterozygous, compound heterozygous, and homozygous state in multiple unrelated individuals from different ethnic backgrounds with FH in published literature (PMID: 1301956, 9026534, 9698020, 10882754, 12436241, 14974088, 15199436, 16250003, 17094996, 17765246, 19318025, 22698793, 22883975, 29353225, 30592178, 33418990); Also known as FH Algeria-1, FH Osaka, and p.E387K due to alternate nomenclature; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9698020, 10882754, 29396260, 29874871, 32759540, 25637381, 25487149, 1301956, 9026534, 15199436, 14974088, 12436241, 16250003, 17094996, 17539906, 17765246, 18700895, 20236128, 19837725, 22698793, 19318025, 22883975, 25911074, 29261184, 29353225, 32163632, 31447099, 33740630, 34037665, 30592178, 33418990, 32719484, 37589137, 37409534, 37128917, 36648309, 33955087, 33994402, 19280064) -

Homozygous familial hypercholesterolemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 22, 2021

proposed classification - variant undergoing re-assessment, contact laboratory -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2022

The p.E408K pathogenic mutation (also known as c.1222G>A), located in coding exon 9 of the LDLR gene, results from a G to A substitution at nucleotide position 1222. The glutamic acid at codon 408 is replaced by lysine, an amino acid with similar properties. This alteration (also referred to as p.E387K) has been reported in multiple unrelated individuals with heterozygous or homozygous familial hypercholesterolemia (FH), has been detected in FH cohorts, and has shown some segregation with disease in families (Hobbs HH et al. Hum. Mutat. 1992;1:445-66; Webb JC et al. J. Lipid Res. 1996;37:368-81; Fouchier SW et al. Hum Mutat. 2005 Dec;26(6):550-6; Tichý L et al. Atherosclerosis. 2012;223:401-8; Chan ML et al. Mol Genet Genomic Med. 2019 02;7(2):e00520; Galiano M et al. J Clin Apher. 2020 Jun;35(3):163-171; Meshkov A et al. Genes (Basel). 2021 01;12(1)). Functional studies indicate that this alteration results in deficient protein function (Hobbs HH et al., 1992; Webb JC et al. 1996; Strøm TB et al. Biochem. Biophys. Res. Commun. 2011;408:642-6). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hypercholesterolemia Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D;.;.;.;.;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Benign	1.1	L;.;.;.;.;L
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0040	D;D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D
Polyphen		0.99	D;.;.;.;.;.
Vest4		0.69
MVP		1.0
MPC		0.52
ClinPred		0.95	D
GERP RS		4.9
Varity_R		0.83
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs137943601; hg19: chr19-11223989; COSMIC: COSV52943360; COSMIC: COSV52943360;