chr19-11111624-G-A

Position:

chr19-11111624-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BS2BA1BP4BP2

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1171G>A (p.Ala391Thr) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes BA1, BS2, BP2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BA1 - FAF = 0.1752 (17.52%) in African exomes (gnomAD v2.1.1); frequency meets BA1 >0.5%BS2 - Case-level data in VCI indicates this variant is identified in heterozygosity in 1894 normolipidemic individuals, as well as in homozygosity in 58 normolipidemic individuals.BP2 - Case-level data present in VCI indicates this variant has been identified to co-occur with Pathogenic LDLR variants in at least 3 index cases with heterozygous FH phenotype.BP4 - REVEL = 0.309; score is below BP4 threshold of <0.50. splicing evaluation is required. Functional data on splicing not available. A) not on limits B) does not create GT C) no nearby GT. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023426/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.080 ( 764 hom., cov: 31)

Exomes 𝑓: 0.048 ( 2184 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:25O:1

Conservation

PhyloP100: -0.270

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP2

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

BP4

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

BS2

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.1171G>A	p.Ala391Thr	missense_variant	8/18	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.1171G>A	p.Ala391Thr	missense_variant	8/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0801

AC:

12192

AN:

152174

Hom.:

765

Cov.:

show subpopulations

Gnomad AFR

AF:

0.179

Gnomad AMI

AF:

0.0253

Gnomad AMR

AF:

0.0437

Gnomad ASJ

AF:

0.0251

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.0449

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0496

Gnomad OTH

AF:

0.0583

GnomAD3 exomes

AF:

0.0434

AC:

10892

AN:

250704

Hom.:

450

AF XY:

0.0408

AC XY:

5527

AN XY:

135630

show subpopulations

Gnomad AFR exome

AF:

0.181

Gnomad AMR exome

AF:

0.0255

Gnomad ASJ exome

AF:

0.0222

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00493

Gnomad FIN exome

AF:

0.0444

Gnomad NFE exome

AF:

0.0487

Gnomad OTH exome

AF:

0.0382

GnomAD4 exome

AF:

0.0475

AC:

69434

AN:

1461152

Hom.:

2184

Cov.:

AF XY:

0.0460

AC XY:

33454

AN XY:

726870

show subpopulations

Gnomad4 AFR exome

AF:

0.188

Gnomad4 AMR exome

AF:

0.0287

Gnomad4 ASJ exome

AF:

0.0229

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00527

Gnomad4 FIN exome

AF:

0.0451

Gnomad4 NFE exome

AF:

0.0496

Gnomad4 OTH exome

AF:

0.0512

GnomAD4 genome

AF:

0.0801

AC:

12198

AN:

152292

Hom.:

764

Cov.:

AF XY:

0.0761

AC XY:

5669

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.179

Gnomad4 AMR

AF:

0.0437

Gnomad4 ASJ

AF:

0.0251

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00393

Gnomad4 FIN

AF:

0.0449

Gnomad4 NFE

AF:

0.0495

Gnomad4 OTH

AF:

0.0577

Alfa

AF:

0.0504

Hom.:

480

Bravo

AF:

0.0855

TwinsUK

AF:

0.0475

AC:

176

ALSPAC

AF:

0.0462

AC:

178

ESP6500AA

AF:

0.173

AC:

762

ESP6500EA

AF:

0.0484

AC:

416

ExAC

AF:

0.0464

AC:

5631

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.0492

EpiControl

AF:

0.0499

ClinVar

Significance: Benign

Submissions summary: Benign:25Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Benign:13

Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Benign, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 23, 2021	The NM_000527.5(LDLR):c.1171G>A (p.Ala391Thr) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes BA1, BS2, BP2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BA1 - FAF = 0.1752 (17.52%) in African exomes (gnomAD v2.1.1); frequency meets BA1 >0.5% BS2 - Case-level data in VCI indicates this variant is identified in heterozygosity in 1894 normolipidemic individuals, as well as in homozygosity in 58 normolipidemic individuals. BP2 - Case-level data present in VCI indicates this variant has been identified to co-occur with Pathogenic LDLR variants in at least 3 index cases with heterozygous FH phenotype. BP4 - REVEL = 0.309; score is below BP4 threshold of <0.50. splicing evaluation is required. Functional data on splicing not available. A) not on limits B) does not create GT C) no nearby GT. -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 22, 2017	- -
Benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	MAF = 0.10 in normolipidemic controls; MAF = 8,7% in 86 Spanish healthy individuals; 0/200 Brazilian (european ancestry) normolipidemic individuals; 0/100 healthy control individuals; 0/77 healthy control individuals -
Benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 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 = 201 6 being homozygotes / Software predictions: Benign -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Mar 22, 2017	- -
Benign, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Aug 22, 2019	- -
Likely benign, criteria provided, single submitter	research	Cardiovascular Biomarker Research Laboratory, Mayo Clinic	Aug 31, 2016	DLCN criteria >=3. -
Likely benign, criteria provided, single submitter	clinical testing	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	Jul 23, 2018	Due to the increased occurrence of the mutation (>= 5%), this variant is classified as likely benign. -

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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	Athena Diagnostics	Mar 21, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Familial hypercholesterolemia

Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 30, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Cohesion Phenomics	Feb 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	Jul 18, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:2Other:1

not provided, no classification provided	in vitro	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2016

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

0.067

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.26

CADD

Benign

5.0

DANN

Benign

0.22

DEOGEN2

Uncertain

0.45

T;.;.;.;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.83

T;T;T;T;T;T

MetaRNN

Benign

0.0035

T;T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-2.1

N;.;.;.;.;N

MutationTaster

Benign

1.0

P;P;P;P;P;P;P

PrimateAI

Benign

0.28

PROVEAN

Benign

0.68

N;N;N;N;N;N

REVEL

Uncertain

0.31

Sift

Benign

0.57

T;T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T

Polyphen

0.0050

B;.;.;.;.;.

Vest4

0.019

MPC

0.24

ClinPred

0.0040

GERP RS

-0.82

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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