rs138477254

Positions:

chr19-11123315-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000527.5(LDLR):c.2282C>T(p.Thr761Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000533 in 1,614,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:14B:4O:1

Conservation

PhyloP100: 3.85

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.828

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.2282C>T	p.Thr761Met	missense_variant	15/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.2282C>T	p.Thr761Met	missense_variant	15/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251242

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000289

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:

0.0000792

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000534

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.0000536

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000671

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:

0.0000647

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000100

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:14Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:1Uncertain:6Benign:2

Uncertain significance, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Uncertain significance, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Uncertain significance, 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 = 2/Software predictions: Conflicting -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Uncertain significance, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 01, 2023	This missense variant (also known as p.Thr740Met in the mature protein) replaces threonine with methionine at codon 761 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant does not disrupt LDLR function (PMID: 25647241). This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 15199436, 16250003, 16542394, 21722902), and in an individual affected with dyslipidemia (PMID: 32041611). This variant has been identified in 13/251242 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jun 02, 2023	- -

not provided

Uncertain:3Benign:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 20, 2023	In the published literature, this variant has been reported in individuals with familial hypercholesterolemia (PMIDs: 1722902 (2011), 16792510 (2006), 15199436 (2004), 21722902 (2011)). Additionally, the variant has been reported to co-occur with other pathogenic variants in individuals with familial hypercholesterolemia (PMIDs: 20428891 (2010), 18325082 (2008)). The frequency of this variant in the general population, 0.00018 (3/16248 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 predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
not provided, no classification provided	in vitro	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Feb 17, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2024	Observed in multiple individuals of different ethnic backgrounds with FH; however, at least two individuals also harbored additional variants in the LDLR gene (PMID: 15199436, 16250003, 16542394, 16792510, 19318025, 20428891, 21722902, 35913489); Observed in an individual with early myocardiac infarction, but normal LDL-C levels who underwent whole exome sequencing (PMID: 25487149, 25647241); Observed in a Dutch population in which carriers of this variant were concluded to have LDL-C levels that were not significantly different from non-carriers (PMID: 20506408, 22390909); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrated no change in LDL uptake in comparison to wild type LDLR protein (PMID: 25647241); 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: 25647241, 16792510, 22390909, 25637381, 16250003, 16542394, 19318025, 21722902, 20428891, 15199436, 27044878, 32041611, 32719484, 25487149, 20506408, 35379577, 35913489, 18325082, 37409534) -

Familial hypercholesterolemia

Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 761 of the LDLR protein (p.Thr761Met). This variant is present in population databases (rs138477254, gnomAD 0.01%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 15199436, 16250003, 16542394, 18325082, 20428891, 22390909, 35379577, 35913489). ClinVar contains an entry for this variant (Variation ID: 161262). 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 80%. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 24, 2023	This missense variant (also known as p.Thr740Met in the mature protein) replaces threonine with methionine at codon 761 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant does not disrupt LDLR function (PMID: 25647241). This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 15199436, 16250003, 16542394, 21722902), and in an individual affected with dyslipidemia (PMID: 32041611). This variant has been identified in 13/251242 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 01, 2018

Variant summary: LDLR c.2282C>T (p.Thr761Met) results in a non-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 4.5e-05 in 246126 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in LDLR Familial Hypercholesterolemia (4.5e-05 vs 0.0013), allowing no conclusion about variant significance. The variant, c.2282C>T, has been reported in the literature in individuals affected with Familial Hypercholesterolemia and myocardial infarction (Thormaehlen_2015, Fouchier_2005, Brusgaard_2006, Amendola_2015). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Thormaehlen_2015). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS x4, pathogenic x1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 10, 2023

The p.T761M variant (also known as c.2282C>T), located in coding exon 15 of the LDLR gene, results from a C to T substitution at nucleotide position 2282. The threonine at codon 761 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in dyslipidemia and myocardial infarction cohorts (Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Fouchier SW et al. Hum Mutat, 2005 Dec;26:550-6; Lombardi MP et al. Genet Test, 2006;10:77-84; Brusgaard K et al. Clin Genet, 2006 Mar;69:277-83; Alonso R et al. Clin Biochem, 2009 Jun;42:899-903; Vaca G et al. Atherosclerosis, 2011 Oct;218:391-6; Thormaehlen AS et al. PLoS Genet, 2015 Feb;11:e1004855; Dron JS et al. BMC Med Genomics, 2020 Feb;13:23). This alteration was detected in a cohort of 29,906 healthy individuals who underwent multigene panel testing (Grzymski JJ et al. Nat Med, 2020 Aug;26:1235-1239). This amino acid position is highly 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. -

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

Benign

0.11

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

D;.;.;.;.;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.86

D;D;D;D;T;D

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.83

D;D;D;D;D;D

MetaSVM

Pathogenic

0.82

MutationAssessor

Uncertain

2.4

M;.;.;.;.;M

MutationTaster

Benign

0.94

D;D;D;D;D;D;D

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.5

D;N;N;N;N;D

REVEL

Pathogenic

0.73

Sift

Benign

0.036

D;D;D;D;D;T

Sift4G

Uncertain

0.056

T;D;T;T;T;T

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.57

MVP

1.0

MPC

0.69

ClinPred

0.47

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.74

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