rs762815611

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 8P and 4B. PP1_StrongBS3PM2PP3PP4

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.1966C>A (p.His656Asn) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (BS3, PP1_Strong, PM2, PP3 and PP4) 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: BS3 - PMID:32015373 - Level 1 assay - study on heterologous cells (CHO-ldlA7), Western blot and FACS assays - results - Normal (95%) cell surface LDLR, LDL-LDLR binding (100%) and uptake (90-95%). ---- functional study is consistent with no damaging effect.PP1_strong - 1 family with 6 informative meiosis is reported by Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.PM2 - PopMax MAF = 0.00002638 (0.0026%) in European non-Finnish exomes (gnomAD v2.1.1).PP3 - REVEL: 0,905.PP4 - Variant meets PM2. Variant is reported in 1 index case fulfills Simon-Broome criteria. LINK:https://erepo.genome.network/evrepo/ui/classification/CA037604/MONDO:0007750/013

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

12

6

Clinical Significance

Uncertain significance reviewed by expert panel P:6U:3B:2

Conservation

PhyloP100: 7.74

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: 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

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

PP1

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

PP3

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

PP4

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

BS3

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.1966C>A	p.His656Asn	missense	Exon 13 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1966C>A	p.His656Asn	missense	Exon 13 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1843C>A	p.His615Asn	missense	Exon 12 of 17	NP_001182728.1	P01130-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1966C>A	p.His656Asn	missense	Exon 13 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.2224C>A	p.His742Asn	missense	Exon 13 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1966C>A	p.His656Asn	missense	Exon 13 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes

Cov.:

32

GnomAD2 exomes

AF:

0.0000119

AC:

3

AN:

251440

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

20

AN:

1461878

Hom.:

0

Cov.:

35

AF XY:

0.0000165

AC XY:

12

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

33480

American (AMR)

AF:

0.00

AC:

0

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

0

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

0

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000171

AC:

19

AN:

1112000

Other (OTH)

AF:

0.0000166

AC:

1

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0

2

3

5

6

8

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.:

32

Alfa

AF:

0.0000417

Hom.:

0

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

2

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

3

3

2

Hypercholesterolemia, familial, 1 (8)

1

-

-

Cardiovascular phenotype (1)

1

-

-

Familial hypercholesterolemia (1)

1

-

-

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.29

D

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

25

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.91

D

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Pathogenic

0.98

D

M_CAP

Pathogenic

0.82

D

MetaRNN

Pathogenic

0.99

D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Pathogenic

3.8

H

PhyloP100

7.7

PrimateAI

Uncertain

0.65

T

PROVEAN

Pathogenic

-6.7

D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0010

D

Sift4G

Uncertain

0.0040

D

Polyphen

0.60

P

Vest4

0.84

MutPred

0.94

Gain of catalytic residue at H656 (P = 0.0819)

MVP

1.0

MPC

0.80

ClinPred

0.99

D

GERP RS

5.4

Varity_R

0.92

gMVP

0.97

Mutation Taster

=4/96

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

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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Other links and lift over

dbSNP: rs762815611; hg19: chr19-11230888; API