rs141155833

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP4BP2

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1868T>C (p.Ile623Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP4, and BP2 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 = 0.00005 (0.005%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). So, PM2 is met. PP4: Variant meets PM2 and is identified in 1 case with Simon-Broome criteria of possible FH from Robarts Research Institute. So, PP4 is met. BP2: 1 individual from Robarts Research Institute with APOB c.10580G>A variant. Phenotype LDL 5.82 mmol/L - Heterozygous phenotype, c.10580G>A - Pathogenic using the general ACMG guidelines. So BP2 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA037264/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:2U:9

Conservation

PhyloP100: 2.21

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

hypercholesterolemia, familial, 1
Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
homozygous familial hypercholesterolemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LDLR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

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

PP4

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

BP2

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.1868T>C	p.Ile623Thr	missense_variant	Exon 13 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.1868T>C	p.Ile623Thr	missense_variant	Exon 13 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251494

AF XY:

0.0000147

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000239

AC:

AN:

1461848

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000306

AC:

AN:

1111972

Other (OTH)

AF:

0.0000166

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000797

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:1Uncertain:4

Apr 28, 2023

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000527.5(LDLR):c.1868T>C (p.Ile623Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP4, and BP2 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 = 0.00005 (0.005%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). So, PM2 is met. PP4: Variant meets PM2 and is identified in 1 case with Simon-Broome criteria of possible FH from Robarts Research Institute. So, PP4 is met. BP2: 1 individual from Robarts Research Institute with APOB c.10580G>A variant. Phenotype LDL 5.82 mmol/L - Heterozygous phenotype, c.10580G>A - Pathogenic using the general ACMG guidelines. So BP2 is met. -

Aug 22, 2019

Robarts Research Institute, Western University

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

- -

Oct 15, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 06, 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.Ile602Thr in the mature protein) replaces isoleucine with threonine at codon 623 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 an individual affected with familial hypercholesterolemia, who also carried a pathogenic APOB variant that could explain the observed phenotype (PMID: 27765764). This variant has also been reported in an individual with elevated levels of LDL-C (PMID: 33303402). This variant has been identified in 6/282894 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. -

Familial hypercholesterolemia

Pathogenic:1Uncertain:2

Mar 20, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 29, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces isoleucine with threonine at codon 623 of the LDLR protein. This variant is also known as p.Ile602Thr in the mature protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with familial hypercholesterolemia, who also carried a pathogenic variant in the APOB gene (PMID: 27765764). This variant has also been reported in an individual with elevated levels of LDL-C (PMID: 33303402). This variant has been identified in 6/282894 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 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 623 of the LDLR protein (p.Ile623Thr). This variant is present in population databases (rs141155833, gnomAD 0.004%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 27765764, 33303402; Invitae). ClinVar contains an entry for this variant (Variation ID: 369855). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not specified

Uncertain:1

Jun 06, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LDLR c.1868T>C (p.Ile623Thr) results in a non-conservative amino acid change located in the LDLR class B repeat (IPR000033) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251494 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1868T>C has been reported in the literature in individuals affected with familial hypercholesterolemia without strong evidence for or against pathogenicity (examples: Guerin_2023, Wang_2016, Gill_2021, Reijman_2023, Internal data). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. Co-occurrence with another pathogenic variant has been reported (APOB c.10580G>A , p.Arg3527Gln) in one individual providing supporting evidence for a benign role (Wang_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33303402, 37607748, 36752612, 27765764). ClinVar contains an entry for this variant (Variation ID: 369855). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Jan 24, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in patients with hypercholesterolemia; one of whom harbored a another variant in the APOB gene (PMID: 33303402, 27765764); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Also known as p.(I602T); This variant is associated with the following publications: (PMID: 33303402, 27765764) -

Cardiovascular phenotype

Uncertain:1

Oct 25, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.I623T variant (also known as c.1868T>C), located in coding exon 13 of the LDLR gene, results from a T to C substitution at nucleotide position 1868. The isoleucine at codon 623 is replaced by threonine, an amino acid with similar properties. This variant (also referred to as p.I602T) has been detected in individuals with features consistent with familial hypercholesterolemia (Wang J et al. Arterioscler. Thromb. Vasc. Biol. 2016;36:2439-2445; Gill PK et al. J Clin Lipidol. 2021 Nov;15(1):79-87; Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

0.010

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.71

D;.;.;.;.;.

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.85

T;T;T;T;T;T

M_CAP

Pathogenic

0.72

MetaRNN

Uncertain

0.68

D;D;D;D;D;D

MetaSVM

Uncertain

0.56

MutationAssessor

Benign

1.3

L;.;.;.;.;L

PhyloP100

2.2

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.1

N;N;N;N;N;N

REVEL

Uncertain

0.58

Sift

Benign

0.061

T;D;T;T;T;T

Sift4G

Benign

0.22

T;T;T;T;T;T

Polyphen

0.20

B;.;.;.;.;.

Vest4

0.45

MVP

1.0

MPC

0.42

ClinPred

0.47

GERP RS

5.4

Varity_R

0.43

gMVP

0.98

Mutation Taster

=31/69

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over