Genetic Variant LDLR:c.1060+10G>C (chr19-11110781-G-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BS2BA1BP2BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1060+10G>C 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 = 0.4446 (44.46%) in European non-Finnish exomes (gnomAD v2.1.1).BS2 - observed in homozygosity in 155 normolipidemic individuals (118 from Color, 22 from INSA, 15 from Western University), as well as in heterozygosity in 376 normolipidemic individuals (297 from Color, 46 INSA, 33 from Western University).BP2 - Variant co-occurs with a Pathogenic LDLR variant (classified by these guidelines) in 6 individuals with a clear heterozygous FH phenotype (LDL-C <8 mmol/L).BP4 - no REVEL, splicing evaluation required. No functional studies variant not on splicing limits, so BP4 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA031460/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.34 ( 10973 hom., cov: 32)

Exomes 𝑓: 0.44 ( 143674 hom. )

Consequence

LDLR
NM_000527.5 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:26

Conservation

PhyloP100: -2.63

Publications

35 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, 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 -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LDLR	NM_000527.5	MANE Select	c.1060+10G>C	intron	N/A	NP_000518.1	P01130-1
LDLR	NM_001195798.2		c.1060+10G>C	intron	N/A	NP_001182727.1	P01130-5
LDLR	NM_001195799.2		c.937+10G>C	intron	N/A	NP_001182728.1	P01130-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1060+10G>C	intron	N/A	ENSP00000454071.1	P01130-1
LDLR	ENST00000252444.10	TSL:1	c.1318+10G>C	intron	N/A	ENSP00000252444.6	J3KMZ9
LDLR	ENST00000558013.5	TSL:1	c.1060+10G>C	intron	N/A	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes

AF:

0.342

AC:

51905

AN:

151968

Hom.:

10986

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0915

Gnomad AMI

AF:

0.350

Gnomad AMR

AF:

0.436

Gnomad ASJ

AF:

0.449

Gnomad EAS

AF:

0.171

Gnomad SAS

AF:

0.391

Gnomad FIN

AF:

0.503

Gnomad MID

AF:

0.446

Gnomad NFE

AF:

0.450

Gnomad OTH

AF:

0.369

GnomAD2 exomes

AF:

0.397

AC:

99142

AN:

249942

AF XY:

0.404

show subpopulations

Gnomad AFR exome

AF:

0.0836

Gnomad AMR exome

AF:

0.422

Gnomad ASJ exome

AF:

0.460

Gnomad EAS exome

AF:

0.174

Gnomad FIN exome

AF:

0.492

Gnomad NFE exome

AF:

0.448

Gnomad OTH exome

AF:

0.419

GnomAD4 exome

AF:

0.436

AC:

636335

AN:

1459836

Hom.:

143674

Cov.:

AF XY:

0.435

AC XY:

316243

AN XY:

726342

show subpopulations

African (AFR)

AF:

0.0759

AC:

2540

AN:

33470

American (AMR)

AF:

0.425

AC:

19020

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.463

AC:

12084

AN:

26118

East Asian (EAS)

AF:

0.145

AC:

5768

AN:

39666

South Asian (SAS)

AF:

0.393

AC:

33885

AN:

86246

European-Finnish (FIN)

AF:

0.479

AC:

24859

AN:

51932

Middle Eastern (MID)

AF:

0.450

AC:

2596

AN:

5764

European-Non Finnish (NFE)

AF:

0.459

AC:

510472

AN:

1111576

Other (OTH)

AF:

0.416

AC:

25111

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

19544

39089

58633

78178

97722

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15094

30188

45282

60376

75470

<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:

0.341

AC:

51882

AN:

152086

Hom.:

10973

Cov.:

AF XY:

0.345

AC XY:

25639

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.0913

AC:

3791

AN:

41532

American (AMR)

AF:

0.436

AC:

6640

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.449

AC:

1559

AN:

3470

East Asian (EAS)

AF:

0.171

AC:

885

AN:

5180

South Asian (SAS)

AF:

0.391

AC:

1884

AN:

4824

European-Finnish (FIN)

AF:

0.503

AC:

5313

AN:

10560

Middle Eastern (MID)

AF:

0.435

AC:

127

AN:

292

European-Non Finnish (NFE)

AF:

0.450

AC:

30590

AN:

67964

Other (OTH)

AF:

0.367

AC:

774

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1575

3149

4724

6298

7873

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

504

1008

1512

2016

2520

<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:

0.321

Hom.:

1476

Bravo

AF:

0.324

Asia WGS

AF:

0.268

AC:

934

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypercholesterolemia, familial, 1 (10)

not specified (9)

Familial hypercholesterolemia (4)

not provided (2)

Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.017

(source)

DANN

Benign

0.67

PhyloP100

-2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Mutation Taster

=27/70

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over