rs45508991

Positions:

chr19-11123210-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4BA1

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.2177C>T (p.Thr726Ile) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes BA1 and BP4 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:BA1 - FAF = 0.008138 (0.8138%) in European (non-Finnish) exomes (gnomAD v2.1.1), so BA1 is Met.BP4 - REVEL = 0.454, it is below 0.50, so splicing evaluation is required.Functional data on splicing not available.A) variant not on limitsB) does not create AGC) variant is exonic and there 1 an AG nearby MES scores: variant cryptic = -1.90, wt cryptic = -1.77, canonical acceptor = 8.76. Ratio variant cryptic/wt cryptic: -1.90/-1.77 = 1.07 --- it is not above 1.1 Ratio variant cryptic/canonical acceptor: -1.90/8.76 --- it is not above 0.9--- BP4 is Met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023649/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.0049 ( 4 hom., cov: 30)

Exomes 𝑓: 0.0073 ( 43 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:28O:1

Conservation

PhyloP100: 0.0910

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 Benign. Variant got -9 ACMG points.

BP4

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

BA1

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 linkuse as main transcript	c.2177C>T	p.Thr726Ile	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.2177C>T	p.Thr726Ile	missense_variant	15/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00495

AC:

753

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000990

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00998

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00789

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00548

AC:

1378

AN:

251244

Hom.:

AF XY:

0.00530

AC XY:

720

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00211

Gnomad ASJ exome

AF:

0.00258

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0112

Gnomad NFE exome

AF:

0.00859

Gnomad OTH exome

AF:

0.00717

GnomAD4 exome

AF:

0.00730

AC:

10674

AN:

1461774

Hom.:

Cov.:

AF XY:

0.00715

AC XY:

5200

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.000777

Gnomad4 AMR exome

AF:

0.00233

Gnomad4 ASJ exome

AF:

0.00321

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.0122

Gnomad4 NFE exome

AF:

0.00847

Gnomad4 OTH exome

AF:

0.00613

GnomAD4 genome

AF:

0.00495

AC:

753

AN:

152256

Hom.:

Cov.:

AF XY:

0.00497

AC XY:

370

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000987

Gnomad4 AMR

AF:

0.00275

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00998

Gnomad4 NFE

AF:

0.00789

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.00654

Hom.:

Bravo

AF:

0.00419

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00791

AC:

ExAC

AF:

0.00624

AC:

758

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00671

EpiControl

AF:

0.00824

ClinVar

Significance: Benign

Submissions summary: Benign:28Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Benign:15

Benign, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Mar 23, 2017	- -
Benign, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	May 24, 2022	The NM_000527.5(LDLR):c.2177C>T (p.Thr726Ile) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes BA1 and BP4 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: BA1 - FAF = 0.008138 (0.8138%) in European (non-Finnish) exomes (gnomAD v2.1.1), so BA1 is Met. BP4 - REVEL = 0.454, it is below 0.50, so splicing evaluation is required. Functional data on splicing not available. A) variant not on limits B) does not create AG C) variant is exonic and there 1 an AG nearby MES scores: variant cryptic = -1.90, wt cryptic = -1.77, canonical acceptor = 8.76. Ratio variant cryptic/wt cryptic: -1.90/-1.77 = 1.07 --- it is not above 1.1 Ratio variant cryptic/canonical acceptor: -1.90/8.76 --- it is not above 0.9 --- BP4 is Met. -
Benign, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 20, 2015	- -
Benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	1Hmz + 1Htz/100 normolipidemic individuals; 0/200 non-FH alleles -
Benign, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Jan 02, 2018	- -
Benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 10, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	research	Cardiovascular Biomarker Research Laboratory, Mayo Clinic	Aug 31, 2016	does not meet required criteria. "Little/No effect" on the LDL receptor activity based on experimental validation. -
Benign, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Benign, 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 = 17/Software predictions: Benign -
Likely benign, criteria provided, single submitter	research	Institute for Integrative and Experimental Genomics, University of Luebeck	-	- -

Familial hypercholesterolemia

Benign:5

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 28, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	Aug 10, 2022	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 12, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 19, 2022	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 04, 2023	Variant summary: LDLR c.2177C>T (p.Thr726Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0055 in 251244 control chromosomes in the gnomAD database, including 4 homozygotes. The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), strongly suggesting that the variant is benign. Twenty-one clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:3Other:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	LDLR: BS2 -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 20, 2022	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 29, 2023	- -
not provided, no classification provided	in vitro	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	-	- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2017

This alteration is classified as 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

0.11

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.12

CADD

Benign

6.0

DANN

Benign

0.96

DEOGEN2

Uncertain

0.57

D;.;.;.;.;.

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.74

T;T;T;T;T;T

MetaRNN

Benign

0.010

T;T;T;T;T;T

MetaSVM

Benign

-0.41

MutationAssessor

Uncertain

2.1

M;.;.;.;.;M

MutationTaster

Benign

1.0

N;N;N;N;N;N;N

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-2.6

D;N;D;D;N;D

REVEL

Uncertain

0.45

Sift

Benign

0.068

T;T;T;D;T;D

Sift4G

Uncertain

0.031

D;D;D;D;T;D

Polyphen

0.021

B;.;.;.;.;.

Vest4

0.25

MVP

0.99

MPC

0.23

ClinPred

0.016

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.10

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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