chr19-11111522-G-A

Position:

• chr19-11111522-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM3 PP3 PP4 PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1069G>A (p.Glu357Lys) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PM3, PS4_moderate, 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 - This variant is absent from gnomAD (gnomAD v2.1.1).PM3 - Variant meets PM2 and is identified in 2 compound heterozygous cases (1 case in PMID:30179711 (Lock et al., 2018) with LDL = 23.89 mmol/L and also LDLR c.2043C>A - Pathogenic by these guidelines; 1 case in PMID:19026292 (Kolansky et al., 2008) with LDL = 16.29 mmol/L and also LDLR c.1775G>A - Pathogenic by these guidelines).PS4_moderate - Variant meets PM2 and is identified in 8 unrelated index cases (3 cases with DLCN criteria>=6 and 1 case with Simon-Broome criteria of possible FH from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 unrelated case fulfilling internationally accepted criteria (Defesche 2000; Goldstein et al. 1995) for definite heterozygous FH published in PMID:11810272 (Fouchier et al., 2001), The Netherlands; 1 unrelated case fulfilling WHO criteria published in PMID:21382890 (van der Graaf et al., 2011), The Netherlands; 1 unrelated case fulfilling WHO criteria published in PMID:10735632 (Lombardi et al., 2000), The Netherlands; 1 unrelated case with DLCN criteria>=6 published in PMID:28502510 (Bañares et al., 2017), Argentina).PP3 - REVEL = 0.976.PP4 - Variant meets PM2 and is identified in at least one index case who fufills clinical criteria for FH (see PS4 for details), after alternative causes for high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585290/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:15 U:1
• Conservation: PhyloP100: 9.88

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 8 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: 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.1069G>A	p.Glu357Lys	missense_variant	8/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1069G>A	p.Glu357Lys	missense_variant	8/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 31

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461212 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726958

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74340

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:15 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:6 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 16, 2023	Criteria applied: PS4_MOD,PM3,PM2_SUP,PP3,PP4 -
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, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Apr 28, 2023	The NM_000527.5(LDLR):c.1069G>A (p.Glu357Lys) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PM3, PS4_moderate, 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 - This variant is absent from gnomAD (gnomAD v2.1.1). PM3 - Variant meets PM2 and is identified in 2 compound heterozygous cases (1 case in PMID: 30179711 (Lock et al., 2018) with LDL = 23.89 mmol/L and also LDLR c.2043C>A - Pathogenic by these guidelines; 1 case in PMID: 19026292 (Kolansky et al., 2008) with LDL = 16.29 mmol/L and also LDLR c.1775G>A - Pathogenic by these guidelines). PS4_moderate - Variant meets PM2 and is identified in 8 unrelated index cases (3 cases with DLCN criteria>=6 and 1 case with Simon-Broome criteria of possible FH from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 unrelated case fulfilling internationally accepted criteria (Defesche 2000; Goldstein et al. 1995) for definite heterozygous FH published in PMID: 11810272 (Fouchier et al., 2001), The Netherlands; 1 unrelated case fulfilling WHO criteria published in PMID: 21382890 (van der Graaf et al., 2011), The Netherlands; 1 unrelated case fulfilling WHO criteria published in PMID: 10735632 (Lombardi et al., 2000), The Netherlands; 1 unrelated case with DLCN criteria>=6 published in PMID: 28502510 (Bañares et al., 2017), Argentina). PP3 - REVEL = 0.976. PP4 - Variant meets PM2 and is identified in at least one index case who fufills clinical criteria for FH (see PS4 for details), after alternative causes for high cholesterol were excluded. -
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 = 12 , family members = 11 with co-segregation / FH-Paris-7 / Software predictions: Damaging -
Uncertain significance, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2024	Observed with a pathogenic variant on the opposite allele (in trans) in two patients with a clinical diagnosis of HoFH (PMID: 19026292, 30179711); 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; Also known as FH Paris-7 and p.(E336K); This variant is associated with the following publications: (PMID: 22390909, 1301956, 28502510, 30179711, 32719484, 33740630, 34037665, 33087929, 33955087, 35177841, 19026292, 11810272, 21382890, 10735632) -

Familial hypercholesterolemia Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 22, 2019	This missense variant (also known as p.Glu336Lys in the mature protein and as FH Paris-7) replaces glutamic acid with lysine at codon 357 in the EGF-like repeat B of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. Experimental functional study has shown that this variant may cause defect in protein transport or recycling (PMID: 1301956). This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 10735632, 11810272, 1301956, 20506408, 21382890, 23833242). This variant has been reported in compound heterozygosity with c.2034C>A (p.Cys681*) in a young child affected with familial hypercholesterolemia and prominent corneal arcus (PMID: 30179711). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Glu357Lys variant in LDLR has been reported in at least 11 individuals with familial hypercholesterolemia, segregated with disease in 6 affected relatives from 1 family (PMID: 15199436), and was absent from large population studies. This variant has also been reported in ClinVar as having conflicting interpretations of pathogenicity (Variation ID: 251649). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP1_moderate, PP3, PS4_supporting (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu357 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 16250003), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 251649). This variant is also known as E336K. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 10735632, 15199436, 28502510, 30179711; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 357 of the LDLR protein (p.Glu357Lys). -

Homozygous familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 07, 2019

The p.Glu357Lys variant in LDLR, also known as p.Glu336Lys or FH Paris 7, has been reported in the heterozygous state at least 10 probands with hypercholestrolemia (Hobbs 1992, Lombardi 2000, Huijgen 2010, Fouchier 2014, Banares 2017) and segregated with disease in at least 4 affected family members (Kusters 2013). In addition, this variant was identified in the compound heterozygous state with another pathogenic variant in a child with a severe presentation. It was inherited from his mother who had borderline high cholesterol (Lock 2018). This variant has been identified in multiple individuals in a large cohort from the Netherlands with mutation carriers (n=27) having mean LDL of 6.51 mmol/L compared to family members who were not carriers of the variant (n=100) with mean LDL of 3.37 mmol/L (Fouchier 2014). This variant is absent from large population studies but has been reported in ClinVar (Variation ID # 251649). Computational prediction tools and conservation analysis are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP Criteria applied: PS4, PM2, PM3, PP1, PP3. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2022

The p.E357K variant (also known as c.1069G>A), located in coding exon 8 of the LDLR gene, results from a G to A substitution at nucleotide position 1069. The glutamic acid at codon 357 is replaced by lysine, an amino acid with similar properties. This variant was detected in a pediatric clinical homozygous familial hypercholesterolemia (FH) case with a second LDLR mutation in trans, as well as in his heterozygous affected father (Lock JH et al. J AAPOS, 2018 Dec;22:467-468). This variant (also described as legacy p.E336K and FH Paris-7) has been reported in numerous FH cohorts, although clinical details were limited in most cases (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Lombardi MP et al. Clin. Genet., 2000 Feb;57:116-24; Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Kolansky DM et al. Am. J. Cardiol., 2008 Dec;102:1438-43; Huijgen R et al. Hum. Mutat., 2010 Jun;31:752-60). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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 majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;.;.;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	H;.;.;.;.;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.91
MutPred		0.91		Gain of methylation at E357 (P = 0.0038);Gain of methylation at E357 (P = 0.0038);.;.;.;Gain of methylation at E357 (P = 0.0038);
MVP		1.0
MPC		0.86
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.93
gMVP		0.99

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: rs879254781; hg19: chr19-11222198;