19-11110781-G-C

Variant names:

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: 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 -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 rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.1060+10G>C		intron_variant	Intron 7 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.1060+10G>C		intron_variant	Intron 7 of 17	1	NM_000527.5	ENSP00000454071.1		P01130-1

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

Significance: Benign

Submissions summary: Benign:26

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Benign:10

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:literature only

- -

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:research

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

22 Hmz + 46 Htz / 95 non-FH individuals; MAF = 49,4% in 86 Spanish healthy individuals -

Jun 08, 2018

Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Due to the increased occurrence of the mutation (>= 5%), this variant is classified as benign. -

Aug 31, 2016

Cardiovascular Biomarker Research Laboratory, Mayo Clinic

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

MAF =<0.3% -

Jun 22, 2017

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 23, 2021

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

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. -

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

not specified

Benign:9

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 02, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 06, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

c.1060+10G>C in intron 7 of LDLR: This variant is not expected to have clinical significance because it has been identified in 38.5% (46591/121050) of total chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs12710260). -

Sep 30, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 04, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LDLR c.1060+7_1060+10delinsCCCC alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. A constituent SNV, c.1060+10G>C of the variant allele was found at a frequency of 0.39 in 281296 control chromosomes in the gnomAD database (v2.1.1), including 23526 homozygotes. The other constituent SNV of this variant allele, c.1060+7T>C was found at a frequency of 0.9999 in control chromosomes in the gnomAD database (v2.1.1), and therefore, near complete overlap of the c.1060+10G>C occurrences can be assumed. The observed frequency of the c.1060+10G>C variant is approximately 311.25 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. To our knowledge, no occurrence of c.1060+7_1060+10delinsCCCC in individuals affected with Familial Hypercholesterolemia and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial hypercholesterolemia

Benign:4

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

GENinCode PLC

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 09, 2023

Cohesion Phenomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Cardiovascular phenotype

Benign:1

Mar 09, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over