rs150673992

Positions:

chr19-11106627-C-T

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.757C>T (p.Arg253Trp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (no codes were applied) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). LINK:https://erepo.genome.network/evrepo/ui/classification/CA023757/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:2U:10B:5O:1

Conservation

PhyloP100: 0.904

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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.757C>T	p.Arg253Trp	missense_variant	5/18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.757C>T	p.Arg253Trp	missense_variant	5/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.000421

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000191

AC:

AN:

251484

Hom.:

AF XY:

0.000154

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000127

AC:

185

AN:

1461850

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00119

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000899

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000433

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00127

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000250

Hom.:

Bravo

AF:

0.000521

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:10Benign:5Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:2Uncertain:6Benign:1

Uncertain significance, criteria provided, single submitter	research	Cardiovascular Biomarker Research Laboratory, Mayo Clinic	Aug 31, 2016	MAF =<0.3%, likely pathogenic based on the integrative in-silico score. "Little/No effect" on the LDL receptor activity based on experimental validation. -
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	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 23, 2021	- -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Uncertain significance, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Uncertain significance, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 07, 2021	The NM_000527.5(LDLR):c.757C>T (p.Arg253Trp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (no codes were applied) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). -
Likely pathogenic, criteria provided, single submitter	research	Institute for Integrative and Experimental Genomics, University of Luebeck	-	- -

not provided

Uncertain:2Other:1

not provided, no classification provided	in vitro	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 11, 2024	The LDLR c.757C>T (p.Arg253Trp) variant has been reported in the published literature in individuals with familial hypercholesterolemia (FH) with high or elevated levels of LDL-C (PMID: 28220743 (2017), 28145427 (2017), 24507775 (2014), 22390909 (2012), 20506408 (2010), 20506408 (2010)), and in individuals with premature myocardial infarction (PMID: 26036859 (2016), 25487149 (2015)). This variant was reported to have no effect on LDL uptake, however further studies are required to determine the global effect of this variant LDLR protein function (PMID: 10882754 (2000)). The frequency of this variant in the general population, 0.001 (26/24970 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R232W); This variant is associated with the following publications: (PMID: 25637381, 26036859, 11462246, 11810272, 22390909, 24507775, 25487149, 27044878, 27153395, 32044282, 20506408, 11005141) -

Familial hypercholesterolemia

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 01, 2023	This missense variant (also known as p.Arg232Trp in the mature protein) replaces arginine with tryptophan at codon 253 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 several individuals affected with familial hypercholesterolemia (PMID: 11005141, 11462246, 11810272, 20506408, 32878475) and in an individual affected with myocardial infarction (PMID: 26036859). This variant occurs at a relatively high frequency in the general population and has been identified in 56/282892 chromosomes (26/24970 African chromosomes) 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. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 30, 2019	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 23, 2024

Variant summary: LDLR c.757C>T (p.Arg253Trp) results in a non-conservative amino acid change located in the class A repeat (IPR002172) of 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 0.00019 in 251484 control chromosomes, predominantly at a frequency of 0.0012 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (0.00019 vs 0.0013), allowing no conclusion about variant significance. Though the variant, c.757C>T, has been reported in the literature in individuals affected with Hypercholesterolemia and/or Early Onset Coronary Artery Disease (e.g., Thiart_2000, Huijgen_2010, Huijgen_2012, Brenne_2016, Do_2015, Raal_2020, Khoo_2000), the variant was not found to co-segregate with Familial Hypercholesterolemia in at least one family (e.g., Thiart_2000), or to meet any of the three proposed criteria for association with Familial Hypercholesterolemia (e.g., Huijgen_2010, Huijgen_2012 and the Jojo Genetics database). At least one publication reports experimental evidence evaluating an impact on protein function, and these results showed no damaging effect of this variant (e.g., Thormaehlen_2015). Co-occurrence with a pathogenic variant has been reported (LDLR c.313+1G>A, Thiart_2000) in a patient with moderate levels of untreated LDL-C (10.5 mmol/L), thus this evidence does not support benign or pathogenic nature of the variant considering LDLR may have semidominant inheritance. The following publications have been ascertained in the context of this evaluation (PMID: 25637381, 26036859, 34906454, 25487149, 20506408, 22390909, 11005141, 32878475, 28145427, 10882754, 25647241). ClinVar contains an entry for this variant (Variation ID: 161261). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Hypercholesterolemia

Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.065

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.84

D;.;.;.;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.10

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;D;D;D

M_CAP

Pathogenic

0.60

MetaRNN

Benign

0.16

T;T;T;T;T

MetaSVM

Uncertain

0.60

MutationAssessor

Benign

-0.56

N;.;.;.;N

PrimateAI

Benign

0.29

PROVEAN

Pathogenic

-5.4

D;D;D;D;D

REVEL

Pathogenic

0.69

Sift

Benign

0.16

T;T;T;T;T

Sift4G

Uncertain

0.049

D;T;T;T;D

Polyphen

1.0

D;.;.;.;.

Vest4

0.73

MVP

1.0

MPC

0.81

ClinPred

0.095

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.30

gMVP

0.81

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