19-11111506-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BS3_SupportingBA1

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR):c.1061-8T>C variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1, BS3_Supporting) 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: PopMax FAF = 0.008564 in African/African American population in gnomAD (gnomAD v2.2.1).BS3_Supporting: Heterozygous patient cells were used for RNA assays (Level 3 experiment) shown normal LDLR transcripts reported from 2 research labs: Bourbon et al, Unidade de Investigacao Cardiovascular, Instituto Nacional de Saude Dr. Ricardo Jorge, Lisboa, Portugal, (PMID 19411563); Holla et al, Medical Genetics Laboratory, Department of Medical Genetics, Rikshospitalet University Hospital, Oslo, Norway, (PMID 19208450). Functional studies is consistent with no damaging effect. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023412/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.0064 ( 3 hom., cov: 31)

Exomes 𝑓: 0.0069 ( 48 hom. )

Consequence

LDLR
NM_000527.5 splice_region, intron

Scores

Splicing: ADA: 0.000006032

Clinical Significance

Benign reviewed by expert panel U:1B:25

Conservation

PhyloP100: -0.0370

Publications

14 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 -9 ACMG points.

BS3

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.1061-8T>C	splice_region intron	N/A	NP_000518.1	P01130-1
LDLR	NM_001195798.2		c.1061-8T>C	splice_region intron	N/A	NP_001182727.1	P01130-5
LDLR	NM_001195799.2		c.938-8T>C	splice_region 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.1061-8T>C	splice_region intron	N/A	ENSP00000454071.1	P01130-1
LDLR	ENST00000252444.10	TSL:1	c.1319-8T>C	splice_region intron	N/A	ENSP00000252444.6	J3KMZ9
LDLR	ENST00000558013.5	TSL:1	c.1061-8T>C	splice_region intron	N/A	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes

AF:

0.00636

AC:

968

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00825

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00432

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00728

Gnomad OTH

AF:

0.00812

GnomAD2 exomes

AF:

0.00548

AC:

1376

AN:

251058

AF XY:

0.00546

show subpopulations

Gnomad AFR exome

AF:

0.00823

Gnomad AMR exome

AF:

0.00312

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.00114

Gnomad FIN exome

AF:

0.00148

Gnomad NFE exome

AF:

0.00793

Gnomad OTH exome

AF:

0.00685

GnomAD4 exome

AF:

0.00691

AC:

10094

AN:

1460636

Hom.:

Cov.:

AF XY:

0.00689

AC XY:

5010

AN XY:

726662

show subpopulations

African (AFR)

AF:

0.0101

AC:

337

AN:

33440

American (AMR)

AF:

0.00347

AC:

155

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00318

AC:

AN:

26110

East Asian (EAS)

AF:

0.000605

AC:

AN:

39654

South Asian (SAS)

AF:

0.00379

AC:

327

AN:

86232

European-Finnish (FIN)

AF:

0.00192

AC:

102

AN:

53024

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00772

AC:

8584

AN:

1111372

Other (OTH)

AF:

0.00698

AC:

421

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

476

952

1429

1905

2381

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

322

644

966

1288

1610

<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:

0.00638

AC:

972

AN:

152306

Hom.:

Cov.:

AF XY:

0.00611

AC XY:

455

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00830

AC:

345

AN:

41578

American (AMR)

AF:

0.00432

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3470

East Asian (EAS)

AF:

0.000579

AC:

AN:

5180

South Asian (SAS)

AF:

0.00311

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00728

AC:

495

AN:

68024

Other (OTH)

AF:

0.00803

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

102

152

203

254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00698

Hom.:

Bravo

AF:

0.00667

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.00714

EpiControl

AF:

0.00818

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypercholesterolemia, familial, 1 (13)

not specified (5)

not provided (4)

Familial hypercholesterolemia (3)

Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.6

(source)

DANN

Benign

0.25

PhyloP100

-0.037

Mutation Taster

=23/74

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000060

dbscSNV1_RF

Benign

0.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over