chr19-11128126-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.2389+41C>A variant is classified as Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BA1 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 24 March 2025. The supporting evidence is as follows: BA1: FAF = 0.01376 (1.376%) in African/African American exomes (gnomAD v4.1.0).BP4: No REVEL, splicing evaluation required. Functional data on splicing not available. A) not on limits. B) Does not create a GT. C) No nearby GT. Variant is not predicted to alter splicing. LINK:https://erepo.genome.network/evrepo/ui/classification/CA040197/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.0098 ( 11 hom., cov: 31)

Exomes 𝑓: 0.0087 ( 60 hom. )

Consequence

LDLR
NM_000527.5 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -2.04

Publications

2 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: Benign. The variant received -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 rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.2389+41C>A		intron_variant	Intron 16 of 17	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.2389+41C>A		intron_variant	Intron 16 of 17	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00981

AC:

1493

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0155

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00498

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000964

Gnomad SAS

AF:

0.00850

Gnomad FIN

AF:

0.00998

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00851

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.00814

AC:

2040

AN:

250664

AF XY:

0.00820

show subpopulations

Gnomad AFR exome

AF:

0.0144

Gnomad AMR exome

AF:

0.00315

Gnomad ASJ exome

AF:

0.00269

Gnomad EAS exome

AF:

0.00109

Gnomad FIN exome

AF:

0.0113

Gnomad NFE exome

AF:

0.00913

Gnomad OTH exome

AF:

0.00851

GnomAD4 exome

AF:

0.00867

AC:

12342

AN:

1423606

Hom.:

Cov.:

AF XY:

0.00871

AC XY:

6188

AN XY:

710356

show subpopulations

African (AFR)

AF:

0.0148

AC:

486

AN:

32736

American (AMR)

AF:

0.00349

AC:

156

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

25906

East Asian (EAS)

AF:

0.000582

AC:

AN:

39526

South Asian (SAS)

AF:

0.0102

AC:

875

AN:

85540

European-Finnish (FIN)

AF:

0.0123

AC:

651

AN:

53106

Middle Eastern (MID)

AF:

0.00985

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.00884

AC:

9518

AN:

1077258

Other (OTH)

AF:

0.00837

AC:

495

AN:

59174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

627

1254

1882

2509

3136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

356

712

1068

1424

1780

<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:

0.00984

AC:

1498

AN:

152250

Hom.:

Cov.:

AF XY:

0.00998

AC XY:

743

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0156

AC:

648

AN:

41548

American (AMR)

AF:

0.00497

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000966

AC:

AN:

5176

South Asian (SAS)

AF:

0.00850

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00998

AC:

106

AN:

10620

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00851

AC:

579

AN:

68014

Other (OTH)

AF:

0.0123

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

144

215

287

359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00374

Hom.:

Bravo

AF:

0.00925

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Uncertain:1Benign:1

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.17

(source)

DANN

Benign

0.56

PhyloP100

-2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(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