chr19-11105625-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.694+25C>T variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code BP4 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: BP4: The variant is not predicted to affect the splicing process by SpliceAI. So, BP4 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA044382/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00044 ( 1 hom. )

Consequence

LDLR
NM_000527.5 intron

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:2B:6

Conservation

PhyloP100: -1.85

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: Uncertain_significance. The variant received -1 ACMG points.

BP4

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.694+25C>T		intron_variant	Intron 4 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.694+25C>T		intron_variant	Intron 4 of 17	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00106

AC:

161

AN:

151906

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00361

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00432

GnomAD2 exomes

AF:

0.000806

AC:

184

AN:

228260

AF XY:

0.000776

show subpopulations

Gnomad AFR exome

AF:

0.00171

Gnomad AMR exome

AF:

0.00217

Gnomad ASJ exome

AF:

0.000118

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000776

Gnomad OTH exome

AF:

0.00125

GnomAD4 exome

AF:

0.000440

AC:

623

AN:

1416870

Hom.:

Cov.:

AF XY:

0.000435

AC XY:

304

AN XY:

699322

show subpopulations

African (AFR)

AF:

0.00156

AC:

AN:

32702

American (AMR)

AF:

0.00227

AC:

AN:

43228

Ashkenazi Jewish (ASJ)

AF:

0.0000403

AC:

AN:

24784

East Asian (EAS)

AF:

0.00

AC:

AN:

39010

South Asian (SAS)

AF:

0.00

AC:

AN:

83202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49514

Middle Eastern (MID)

AF:

0.00515

AC:

AN:

4076

European-Non Finnish (NFE)

AF:

0.000348

AC:

377

AN:

1081990

Other (OTH)

AF:

0.00129

AC:

AN:

58364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

112

140

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00106

AC:

161

AN:

152024

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.00162

AC:

AN:

41480

American (AMR)

AF:

0.00361

AC:

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

67968

Other (OTH)

AF:

0.00427

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000627

Hom.:

Bravo

AF:

0.00137

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Uncertain:2Benign:1

Apr 28, 2023

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000527.5(LDLR):c.694+25C>T variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code BP4 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: BP4: The variant is not predicted to affect the splicing process by SpliceAI. So, BP4 is met. -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:literature only

- -

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

- -

not provided

Benign:2

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Familial hypercholesterolemia

Benign:2

Apr 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 09, 2019

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Jan 14, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.82

(source)

DANN

Benign

0.85

PhyloP100

-1.8

PromoterAI

0.053

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over