rs370471092

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PS4_SupportingPP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1057G>A (p.Glu353Lys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PS4_Supporting and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 31 January 2025. The supporting evidence is as follows: PM2: PopMax MAF= 0.00002 (0.002%) in European (Non-Finnish) in genomes+exomes (gnomAD v4.1.0). PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 4 cases (1 with possible FH by Simon Broome criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; 1 with DLCN score >=6 from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 case in PMID 33994402 (Huang et al., 2022), Taiwan, and 1 case in PMID 34998859 (Pillai et al., 2022), India, with country-specific FH criteria), after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023410/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:11O:1

Conservation

PhyloP100: 4.61

Variant links:

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]

LDLR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 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.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.1057G>A	p.Glu353Lys	missense_variant	Exon 7 of 18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.1057G>A	p.Glu353Lys	missense_variant	Exon 7 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000599

AC:

AN:

250574

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135570

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1460818

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

726754

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:1Uncertain:4

Nov 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 17, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant (also known as p.Glu332Lys in the mature protein) replaces glutamic acid with lysine at codon 353 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 11810272, 15823288, 20506408; Huang et al, 2021, doi.org/10.5551/jat.62773), as well as in an individual affected with premature myocardial infarction (PMID: 30971288). This variant has also been identified in 16/281978 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Familial hypercholesterolemia

Pathogenic:1Uncertain:4

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 16, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamic acid with lysine at codon 353 of the LDLR protein. This variant is also known as p.Glu332Lys in the mature protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. A functional study using transfected HeLa cells has shown inconclusive results regarding this variant's impact on LDLR expression (PMID: 25647241). This variant has been reported in four individuals affected with familial hypercholesterolemia (PMID: 11810272, 15823288, 20506408, 33994402, 34998859), as well as in one individual affected with premature myocardial infarction (PMID: 30971288). This variant has been identified in 16/281978 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Sep 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 353 of the LDLR protein (p.Glu353Lys). This variant is present in population databases (rs370471092, gnomAD 0.03%). This missense change has been observed in individual(s) with familial hypercholesterolemia and myocardial infarction (PMID: 11810272, 15823288, 20506408, 25647241, 27828139, 27878139, 30971288). This variant is also known as p.Glu332Lys. ClinVar contains an entry for this variant (Variation ID: 161275). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (PMID: 25647241). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Aug 13, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LDLR c.1057G>A (p.Glu353Lys) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 250574 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (6e-05 vs 0.0013), allowing no conclusion about variant significance. c.1057G>A has been reported in the literature in the heterozygous state in multiple individuals affected with Familial Hypercholesterolemia (example, Kusters_2013, Pillai_2022, Reijman_2023) however it has also been observed in at least 1 person with a history of myocardial infarction but no significant elevation in LDL-C (example, Thormaehlen_2015). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity and was considered an "unclear" result by the authors (example, Thormaehlen_2015). The following publications have been ascertained in the context of this evaluation (PMID: 23833242, 34998859, 36752612, 25647241). ClinVar contains an entry for this variant (Variation ID: 161275). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

May 02, 2023

Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This missense change has been observed in individual(s) with familial hypercholesterolemia and myocardial infarction .This variant replaces glutamic acid with lysine at codon 353 of the LDLR protein. -

not provided

Uncertain:1Other:1

Oct 09, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.1057G>A (p.Glu353Lys) variant (also known as E332K) has been reported in the published literature in multiple individuals with familial hypercholesterolemia (FH) (PMIDs: 34998859 (2022), 33994402 (2021), 32041611 (2020), 28502495 (2017), 15823288 (2005), 11810272 (2001)) and myocardial infarction (PMIDs: 30971288 (2019), 25647241 (2015), 25487149 (2015)). However, in some individuals with FH or myocardial infarction, this variant is found to be associated with normal or modestly increased LDL-C levels (PMIDs: 25647241 (2015), 20506408 (2010)). A functional study characterized this variant as having an unclear effect on LDLR function and expression (PMID: 25647241 (2015)). The frequency of this variant in the general population, 0.00035 (7/19946 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Dept. of Genetics and Pharmacogenomics, Merck Research Labs

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Hypercholesterolemia

Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Cardiovascular phenotype

Uncertain:1

Jun 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E353K variant (also known as c.1057G>A), located in coding exon 7 of the LDLR gene, results from a G to A substitution at nucleotide position 1057. The glutamic acid at codon 353 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in familial hypercholesterolemia (FH) cohorts (Fouchier SW et al. Hum Genet, 2001 Dec;109:602-15; Huijgen R et al. Hum Mutat, 2010 Jun;31:752-60; Chiou KR et al. J Clin Lipidol 2017 Jan;11:386-393.e6). This amino acid position is well 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

Benign

0.097

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.29

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

D;.;.;.;.;.

Eigen

Benign

-0.058

Eigen_PC

Benign

-0.016

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D;D;D

M_CAP

Pathogenic

0.46

MetaRNN

Uncertain

0.57

D;D;D;D;D;D

MetaSVM

Uncertain

0.63

MutationAssessor

Benign

1.3

L;.;.;.;.;L

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.8

N;N;N;N;N;N

REVEL

Uncertain

0.62

Sift

Benign

0.19

T;T;T;T;T;T

Sift4G

Benign

0.30

T;T;T;T;T;T

Polyphen

0.36

B;.;.;.;.;.

Vest4

0.42

MVP

1.0

MPC

0.26

ClinPred

0.11

GERP RS

3.0

Varity_R

0.32

gMVP

0.95

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over