rs199570811

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS4PS3_SupportingPM2PVS1PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.261G>A (p.Trp87Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PS4, PM2, PP4 and PS3_Supporting) 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: PVS1 - Variant is nonsense, causing a premature stop at codon 87. It is upstream of amino acid 830, so PVS1 is Met.PS4 - Variant meets PM2. Identified in 10 FH index cases with Dutch Lipid Clinical Network score 10.3 ± 4.1 (Mean ± standard deviation of DLCN score) from PMID:21990180.PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1).PP4 - Variant meets PM2. Identified in 10 FH index cases with Dutch Lipid Clinical Network score 10.3 ± 4.1 (Mean ± standard deviation of DLCN score) from PMID:21990180.PS3_supporting - Level 3 assays: PMID 21990180: Htz patient lymphocytes, FACS and CLSM assays - results - FACS: 40% cell surface LDLR; 60% LDL-LDLR binding; 75% uptake, CLSM: 50-60% cell surface LDLR and LDL-LDLR binding ---- Results are below 85% of wild-type, so PS3_supporting is Met LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584814/MONDO:0007750/013

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LDLR
NM_000527.5 stop_gained

Scores

5

1

1

Clinical Significance

Pathogenic reviewed by expert panel P:7

Conservation

PhyloP100: 7.89

Publications

6 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: Pathogenic. The variant received 16 ACMG points.

PVS1

For more information check the summary or visit ClinGen Evidence Repository.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP4

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.261G>A	p.Trp87*	stop_gained	Exon 3 of 18	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.261G>A	p.Trp87*	stop_gained	Exon 3 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

Cov.:

31

GnomAD4 exome

AF:

6.84e-7

AC:

1

AN:

1461756

Hom.:

0

Cov.:

31

AF XY:

0.00

AC XY:

0

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

33476

American (AMR)

AF:

0.00

AC:

0

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

0

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

0

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

1

AN:

1111930

Other (OTH)

AF:

0.00

AC:

0

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0

0

1

1

2

2

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

0

2

4

6

8

10

<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

Cov.:

31

Alfa

AF:

0.00

Hom.:

0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:5

-

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:literature only

- -

Jun 07, 2021

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000527.5(LDLR):c.261G>A (p.Trp87Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PS4, PM2, PP4 and PS3_Supporting) 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: PVS1 - Variant is nonsense, causing a premature stop at codon 87. It is upstream of amino acid 830, so PVS1 is Met. PS4 - Variant meets PM2. Identified in 10 FH index cases with Dutch Lipid Clinical Network score 10.3 ± 4.1 (Mean ± standard deviation of DLCN score) from PMID: 21990180. PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1). PP4 - Variant meets PM2. Identified in 10 FH index cases with Dutch Lipid Clinical Network score 10.3 ± 4.1 (Mean ± standard deviation of DLCN score) from PMID: 21990180. PS3_supporting - Level 3 assays: PMID 21990180: Htz patient lymphocytes, FACS and CLSM assays - results - FACS: 40% cell surface LDLR; 60% LDL-LDLR binding; 75% uptake, CLSM: 50-60% cell surface LDLR and LDL-LDLR binding ---- Results are below 85% of wild-type, so PS3_supporting is Met -

not provided

Pathogenic:1

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LDLR: PVS1, PM2, PP4:Moderate, PS4:Moderate, PS3:Supporting -

Familial hypercholesterolemia

Pathogenic:1

Aug 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Trp87*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with LDLR-related conditions (PMID: 19318025, 34456049). ClinVar contains an entry for this variant (Variation ID: 251100). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

D

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

39

DANN

Uncertain

1.0

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.97

D

PhyloP100

7.9

Vest4

0.90

GERP RS

5.7

Mutation Taster

=0/200

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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Other links and lift over

dbSNP: rs199570811; hg19: chr19-11213410; API